Article

Fibrillin-1 Genotype Is Associated With Aortic Stiffness and Disease Severity in Patients With Coronary Artery Disease

February 2002
Circulation 105(7):810-5

February 2002
105(7):810-5

DOI:10.1161/hc0702.104129

Source
PubMed

Authors:

Tanya Medley

Murdoch Children's Research Institute

William Wang

The University of Queensland

Show all 6 authorsHide

Elevated pulse pressure is associated strongly with adverse cardiovascular outcome; however, the genetic basis of this condition is unknown. This study examined whether genotypic variation in the extracellular matrix protein fibrillin-1, the Marfan gene, was associated with aortic stiffening and therefore could contribute to cardiovascular risk associated with pulse pressure elevation in coronary disease. Patients (n=145; 113 men), 62+/-9 years of age (mean+/-SD), with angiographically confirmed coronary disease, were studied. Carotid applanation tonometry was used to assess central blood pressures, and in conjunction with Doppler velocimetry, to assess aortic input and characteristic impedance. Fibrillin-1 genotype was characterized by a variable nucleotide tandem repeat and 2 single-nucleotide polymorphisms. The variable nucleotide tandem repeat was a good predictor of underlying haplotypes with 3 genotypes (2-2, 2-4, and 2-3) accounting for 86% of the population. The 2-3 genotype had higher input impedance (P=0.002), characteristic impedance (P=0.005), and carotid pulse pressure (P=0.002) compared with the 2-2 and 2-4 genotypes. Disease severity assessed by previous angioplasties and the number of patients with a stenosis >90% was also greater in the 2-3 genotype. Furthermore, in a multivariate analysis, fibrillin-1 genotype and central pulse pressure were independent of conventional risk factors in determining coronary disease severity. There was no difference in age, sex ratio, body mass index, smoking status, cholesterol level, or medication among the 3 genotypes. Although a causative link has not been shown, these data are consistent with an important role for fibrillin-1 genotype in cardiovascular risk associated with large-artery stiffening and pulse pressure elevation in individuals with coronary disease.

No differences in FBN1 genotype between men with and without abdominal aortic aneurysm

Article

Full-text available

Jan 2023
BMC Cardiovasc Disord

Background Abdominal aortic aneurysm (AAA) is an aortic enlargement in which the transverse diameter reaches at least 30 mm. Certain risk factors, such as age, male gender, and smoking, are well known; however, less is known about the genetic factors involved. Fibrillin-1 (FBN1) is a protein that coordinates the deposition of elastin fibres in the extracellular matrix and is therefore likely to affect the elastic properties in the aortic wall. Previously studies have found associations between the FBN1-2/3 genotype and arterial stiffness, but how different FBN1 genotypes, AAA, and arterial stiffness are related has been less frequently investigated. Aim This study aimed to investigate whether there is a difference in FBN1 genotype between men with and without AAA. A further aim was to study whether the FBN1 genotype affects arterial wall stiffness differently in men with and without AAA. Methods Pulse wave velocity and FBN1 genotyping were performed in 229 men (159 with AAA, 70 without AAA). Participants were recruited from ultrasound AAA surveillance programs or ongoing ultrasound screening programs from 2011 to 2016. Results The distribution of the FBN1 genotype in the AAA and control groups were as follows: FBN1-2/2: 62% vs. 64%; FBN1-2/3: 8% vs. 14%; and FBN1-2/4: 30% vs. 21%, respectively. Men with AAA and FBN1-2/2 had increased central pulse wave velocity ( p < 0.005) compared to the control group (those without AAA) with the FBN1-2/2 genotype. Conclusion No differences were found with respect to FBN1 genotypes between men with and without AAA. The development of AAA in men does not appear to be linked to a specific FBN1 genotype. Nevertheless, men with FBN1-2/2 and AAA have increased central arterial stiffness compared to men with the same FBN1 genotype but without AAA.

Higher blood pressure in elderly hypertensive females, with increased arterial stiffness and blood pressure in females with the Fibrillin-1 2/3 genotype

Article

Full-text available

Apr 2020
BMC Cardiovasc Disord

Background: Elderly patients have a relatively high cardiovascular risk due to increased arterial stiffness, elevated blood pressure and decreased amounts of elastin in the arteries. The composition of the media layer in the arterial wall, comprising elastin, collagen, smooth muscle cells, proteoglycans, fibronectin and fibrillin-1, influences its mechanical properties. Mutations in the fibrillin-1 gene leads to increased aortic stiffness, elevated pulse pressure and aortic root dilatation. This study investigates whether there is a sex difference among hypertensive elderly patients regarding blood pressure, arterial stiffness and fibrillin-1 genotypes. Methods: A total of 315 hypertensive subjects (systolic blood pressure > 140 mmHg) were included in this study (155 men and 160 women aged 71-88 years). Aortic pulse wave velocity and augmentation index were determined using SphygmoCor, and brachial blood pressure was measured using an oscillometric technique. Fibrillin-1 was genotyped by polymerase chain reaction and with a capillary electrophoresis system. Results: Females showed a significantly higher peripheral mean arterial pressure (females; 107.20 mmHg, males 101.6 mmHg, p = 0.008), central mean arterial pressure (females; 107.2 mmHg, males 101.6 mmHg p = 0.008), central systolic blood pressure (females; 148.1 mmHg, males 139.2 mmHg, p < 0.001) and central pulse pressure (females; 68.9 mmHg, males 61.6 mmHg, p = 0.035) than males. Females with the Fibrillin-1 2/3 genotype showed a significantly higher augmentation index (FBN1 2/3; 39.9%, FBN1 2/2 35.0%, FBN1 2/4 35.8, p = 0.029) and systolic blood pressure (FBN1 2/3; 174.6 mmHg, FBN1 2/2168.9 mmHg, FBN1 2/4169.9 mmHg, p = 0.025) than females with the 2/2 and 2/4 genotypes. Conclusion: The findings of this study may indicate that hypertensive elderly females, especially elderly females with Fibrillin-1 2/3, have increased systolic blood pressure and arterial stiffness.

Animal models of atherosclerosis

Article

May 2017

An ideal animal model of atherosclerosis resembles human anatomy and pathophysiology and has the potential to be used in medical and pharmaceutical research to obtain results that can be extrapolated to human medicine. Moreover, it must be easy to acquire, can be maintained at a reasonable cost, is easy to handle and shares the topography of the lesions with humans. In general, animal models of atherosclerosis are based on accelerated plaque formation due to a cholesterol-rich/Western-type diet, manipulation of genes involved in the cholesterol metabolism, and the introduction of additional risk factors for atherosclerosis. Mouse and rabbit models have been mostly used, followed by pigs and non-human primates. Each of these models has its advantages and limitations. The mouse has become the predominant species to study experimental atherosclerosis because of its rapid reproduction, ease of genetic manipulation and its ability to monitor atherogenesis in a reasonable time frame. Both Apolipoprotein E deficient (ApoE-/-) and LDL-receptor (LDLr) knockout mice have been frequently used, but also ApoE/LDLr double-knockout, ApoE3-Leiden and PCSK9-AAV mice are valuable tools in atherosclerosis research. However, a great challenge was the development of a model in which intra-plaque microvessels, haemorrhages, spontaneous atherosclerotic plaque ruptures, myocardial infarction and sudden death occur consistently. These features are present in ApoE-/-Fbn1C1039G+/- mice, which can be used as a validated model in pre-clinical studies to evaluate novel plaque-stabilizing drugs.

Elastin fragmentation in atherosclerotic mice leads to intraplaque neovascularization, plaque rupture, myocardial infarction, stroke, and sudden death

Article

Full-text available

Feb 2014
EUR HEART J

There is a need for animal models of plaque rupture. We previously reported that elastin fragmentation, due to a mutation (C1039G(+/-)) in the fibrillin-1 (Fbn1) gene, promotes atherogenesis and a highly unstable plaque phenotype in apolipoprotein E deficient (ApoE(-/-)) mice on a Western-type diet (WD). Here, we investigated whether plaque rupture occurred in ApoE(-/-)Fbn1(C1039G+/-) mice and was associated with myocardial infarction, stroke, and sudden death. Female ApoE(-/-)Fbn1(C1039G+/-) and ApoE(-/-) mice were fed a WD for up to 35 weeks. Compared to ApoE(-/-) mice, plaques of ApoE(-/-)Fbn1(C1039G+/-) mice showed a threefold increase in necrotic core size, augmented T-cell infiltration, a decreased collagen I content (70 ± 10%), extensive neovascularization, intraplaque haemorrhage, and a significant increase in matrix metalloproteinase-2, -9, -12, and -13 expression or activity. Plaque rupture was observed in 70% of ascending aortas and in 50% of brachiocephalic arteries of ApoE(-/-)Fbn1(C1039G+/-) mice. In ApoE(-/-) mice, plaque rupture was not seen in ascending aortas and only in 10% of brachiocephalic arteries. Seventy percent of ApoE(-/-)Fbn1(C1039G+/-) mice died suddenly, whereas all ApoE(-/-) mice survived. ApoE(-/-)Fbn1(C1039G+/-) mice showed coronary plaques and myocardial infarction (75% of mice). Furthermore, they displayed head tilt, disorientation, and motor disturbances (66% of cases), disturbed cerebral blood flow (73% of cases; MR angiograms) and brain hypoxia (64% of cases), indicative of stroke. Elastin fragmentation plays a key role in plaque destabilization and rupture. ApoE(-/-)Fbn1(C1039G+/-) mice represent a unique model of acute plaque rupture with human-like complications.

Acetylsalicylic Acid Reduces Passive Aortic Wall Stiffness and Cardiovascular Remodelling in a Mouse Model of Advanced Atherosclerosis

Article

Full-text available

Dec 2021
INT J MOL SCI

Acetylsalicylic acid (ASA) is widely used in secondary prevention of cardiovascular (CV) disease, mainly because of its antithrombotic effects. Here, we investigated whether ASA can prevent the progression of vessel wall remodelling, atherosclerosis, and CV complications in apolipoprotein E deficient (ApoE−/−) mice, a model of stable atherosclerosis, and in ApoE−/− mice with a mutation in the fibrillin-1 gene (Fbn1C1039G+/−), which is a model of elastic fibre fragmentation, accompanied by exacerbated unstable atherosclerosis. Female ApoE−/− and ApoE−/−Fbn1C1039G+/− mice were fed a Western diet (WD). At 10 weeks of WD, the mice were randomly divided into four groups, receiving either ASA 5 mg/kg/day in the drinking water (ApoE−/− (n = 14), ApoE−/−Fbn1C1039G+/− (n = 19)) or plain drinking water (ApoE−/− (n = 15), ApoE−/−Fbn1C1039G+/− (n = 21)) for 15 weeks. ApoE−/−Fbn1C1039G+/− mice showed an increased neutrophil–lymphocyte ratio (NLR) compared to ApoE−/− mice, and this effect was normalised by ASA. In the proximal ascending aorta wall, ASA-treated ApoE−/−Fbn1C1039G+/− mice showed less p-SMAD2/3 positive nuclei, a lower collagen percentage and an increased elastin/collagen ratio, consistent with the values measured in ApoE−/− mice. ASA did not affect plaque progression, incidence of myocardial infarction and survival of ApoE−/−Fbn1C1039G+/− mice, but systolic blood pressure, cardiac fibrosis and hypertrophy were reduced. In conclusion, ASA normalises the NLR, passive wall stiffness and cardiac remodelling in ApoE−/−Fbn1C1039G+/− mice to levels observed in ApoE−/− mice, indicating additional therapeutic benefits of ASA beyond its classical use.

Meary Angle for the prediction of mitral valve prolapse risk in non-syndromic patients with pes planus, a cross-sectional study

Preprint

Full-text available

Feb 2022

Objectives: Mitral Valve prolapse (MVP) is the commonest valvular abnormality. There is a reported association between pes planus (PP) and MVP in some syndromes such as Marfan, however, this association has not been tested in non-syndromic cases. The primary outcome of this study is to measure the prevalence of MVP in a population of patients with PP. The secondary outcome parameter is to determine if the Meary angle (MA), a measure of severity of flat foot, can be effectively used in the prediction of the presence of MVP. Forty-One patients with PP have been screened with lateral x-ray foot to determine MA and echocardiography to determine the presence and grade of MVP. Results: 88% of screened patients were diagnosed with MVP. MA was correlated with the grade of MVP and showed high diagnostic accuracy (Sensitivity 100% and Specificity 90%) in predicting MVP risk when higher than 5. Children with PP are at a higher risk of MVP than the general population. Utilizing MA in such a specific population for the determination of patients at the higher need for echocardiography seems to be a useful strategy to diagnose MVP in those patients.

Vascular Stiffness in Aging and Disease

Article

Full-text available

Dec 2021

The goal of this review is to provide further understanding of increased vascular stiffness with aging, and how it contributes to the adverse effects of major human diseases. Differences in stiffness down the aortic tree are discussed, a topic requiring further research, because most prior work only examined one location in the aorta. It is also important to understand the divergent effects of increased aortic stiffness between males and females, principally due to the protective role of female sex hormones prior to menopause. Another goal is to review human and non-human primate data and contrast them with data in rodents. This is particularly important for understanding sex differences in vascular stiffness with aging as well as the changes in vascular stiffness before and after menopause in females, as this is controversial. This area of research necessitates studies in humans and non-human primates, since rodents do not go through menopause. The most important mechanism studied as a cause of age-related increases in vascular stiffness is an alteration in the vascular extracellular matrix resulting from an increase in collagen and decrease in elastin. However, there are other mechanisms mediating increased vascular stiffness, such as collagen and elastin disarray, calcium deposition, endothelial dysfunction, and the number of vascular smooth muscle cells (VSMCs). Populations with increased longevity, who live in areas called “Blue Zones,” are also discussed as they provide additional insights into mechanisms that protect against age-related increases in vascular stiffness. Such increases in vascular stiffness are important in mediating the adverse effects of major cardiovascular diseases, including atherosclerosis, hypertension and diabetes, but require further research into their mechanisms and treatment.

Rare Causes of Arterial Hypertension and Thoracic Aortic Aneurysms—A Case-Based Review

Article

Full-text available

Mar 2021

Thoracic aortic aneurysms may result in dissection with fatal consequences if undetected. A young male patient with no relevant familial history, after having been investigated for hypertension, was diagnosed with an ascending aortic aneurysm involving the aortic root and the proximal tubular segment, associated with a septal atrial defect. The patient underwent a Bentall surgery protocol without complications. Clinical examination revealed dorso–lumbar scoliosis and no other signs of underlying connective tissue disease. Microscopic examination revealed strikingly severe medial degeneration of the aorta, with areas of deep disorganization of the medial musculo–elastic structural units and mucoid material deposition. Genetic testing found a variant of unknown significance the PRKG1 gene encoding the protein kinase cGMP-dependent 1, which is important in blood pressure regulation. There may be genetic links between high blood pressure and thoracic aortic aneurysm determinants. Hypertension was found in FBN1 gene mutations encoding fibrillin and in PRKG1 mutations. Possible mechanisms involving the renin–angiotensin system, the role of oxidative stress, osteopontin, epigenetic modifications and other genes are reviewed. Close follow-up and strict hypertension control are required to reduce the risk of dissection. Hypertension, scoliosis and other extra-aortic signs suggesting a connective tissue disease are possible clues for diagnosis.

Caught between a “Rho” and a hard place: are CCN1/CYR61 and CCN2/CTGF the arbiters of microvascular stiffness?

Article

Aug 2019

Brahim Chaqour

The extracellular matrix (ECM) is a deformable dynamic structure that dictates the behavior, function and integrity of blood vessels. The composition, density, chemistry and architecture of major globular and fibrillar proteins of the matrisome regulate the mechanical properties of the vasculature (i.e., stiffness/compliance). ECM proteins are linked via integrins to a protein adhesome directly connected to the actin cytoskeleton and various downstream signaling pathways that enable the cells to respond to external stimuli in a coordinated manner and maintain optimal tissue stiffness. However, cardiovascular risk factors such as diabetes, dyslipidemia, hypertension, ischemia and aging compromise the mechanical balance of the vascular wall. Stiffening of large blood vessels is associated with well-known qualitative and quantitative changes of fibrillar and fibrous macromolecules of the vascular matrisome. However, the mechanical properties of the thin-walled microvasculature are essentially defined by components of the subendothelial matrix. Cellular communication network (CCN) 1 and 2 proteins (aka Cyr61 and CTGF, respectively) of the CCN protein family localize in and act on the pericellular matrix of microvessels and constitute primary candidate markers and regulators of microvascular compliance. CCN1 and CCN2 bind various integrin and non-integrin receptors and initiate signaling pathways that regulate connective tissue remodeling and response to injury, the associated mechanoresponse of vascular cells, and the subsequent inflammatory response. The CCN1 and CCN2 genes are themselves responsive to mechanical stimuli in vascular cells, wherein mechanotransduction signaling converges into the common Rho GTPase pathway, which promotes actomyosin-based contractility and cellular stiffening. However, CCN1 and CCN2 each exhibit unique functional attributes in these processes. A better understanding of their synergistic or antagonistic effects on the maintenance (or loss) of microvascular compliance in physiological and pathological situations will assist more broadly based studies of their functional properties and translational value.

Erectile dysfunction : a syndrome heralds heart attacks

Article

Dec 2011

Tarek Abdel rahman

GWAB: A web server for the network-based boosting of human genome-wide association data

Article

Full-text available

Apr 2017
NUCLEIC ACIDS RES

During the last decade, genome-wide association studies (GWAS) have represented a major approach to dissect complex human genetic diseases. Due in part to limited statistical power, most studies identify only small numbers of candidate genes that pass the conventional significance thresholds (e.g. P ≤ 5 × 10-8). This limitation can be partly overcome by increasing the sample size, but this comes at a higher cost. Alternatively, weak association signals can be boosted by incorporating independent data. Previously, we demonstrated the feasibility of boosting GWAS disease associations using gene networks. Here, we present a web server, GWAB (www.inetbio.org/gwab), for the network-based boosting of human GWAS data. Using GWAS summary statistics (P-values) for SNPs along with reference genes for a disease of interest, GWAB reprioritizes candidate disease genes by integrating the GWAS and network data. We found that GWAB could more effectively retrieve disease-associated reference genes than GWAS could alone. As an example, we describe GWAB-boosted candidate genes for coronary artery disease and supporting data in the literature. These results highlight the inherent value in sub-threshold GWAS associations, which are often not publicly released. GWAB offers a feasible general approach to boost such associations for human disease genetics.

The reverse remodeling of the aorta in patients after renal transplantation - the value of aortic stiffness index: prospective echocardiographic study

Article

Full-text available

Jan 2017
BMC Nephrol

Background Atherosclerosis is regarded as a combination of two major separate diseases: atherosis and sclerosis. Sclerotic component depends on deterioration of elastic properties of the aortic wall and is called aortic stiffness. The most valuable, non-invasive method of aortic stiffness assessment is echocardiography, which allows to calculate the aortic stiffness index (ASI). ASI is an independent predictor of all-cause and cardiovascular mortality in different groups of patients. The main aim of study was the assessment of the aortic reverse remodeling in patients with end-stage renal disease (ESRD) after renal transplantation (RT). Methods Study group involved 42 patients aged 43.3 ± 12.6 years, including 19 women aged 49.9 ± 10.9 years and 23 men aged 41.5 ± 12.91 years, who have undergone RT from non-related renal transplant donors, The study protocol has been consisted of 5 stages: 1 week after RT, 3 months after RT, 6 months after RT, 1 year after RT and 3 years after RT. The echocardiographic examination was performed and measurements of Aomax, Aomin were done. On the base of obtained parameters ASI, aortic distensibility (AD) and aortic strain (AS) were calculated according to adequate formulas. ResultsThe improvement of indices characterizing the elastic properties of aorta were noted. These changes attained the statistically significant level only at the end of the observation. ASI just after RT was equal – 4.65 ± 1.58, three months after RT – 4.54 ± 1.49, six months after RT – 4.59 ± 1.61, one year after RT – 4.35 ± 1.21 and three years after RT – 3.35 ± 1.29, while AD reached respectively – 6.55 ± 3.76 cm2/dyn−110−6 just after RT, − 6.38 ± 3.42 cm2/dyn−110−6 three months after RT, − 6.53 ± 3.60 cm2/dyn−110−6 six months after RT, − 6.48 ± 2.79 cm2/dyn−110−6 one year after RT and – 8.03 ± 3.95 cm2/dyn−110−6 three years after RT. Noted AS values were equal – 6.61 ± 4.05%, just after RT, − 6.40 ± 3.58% three months after RT, − 6.56 ± 3.76%, six months after RT, − 6.45 ± 2.80% one year after RT, − 8.01 ± 3.97%. and three years after RT. The exact analysis of parameters concerning aortic function showed that to achieve ASI, AD and AS improvement, long time was needed, because the most significant changes of these indices were observed only between 1 year and 3 years after RT. Conclusions There is a relationship between renal transplantation and improvement of the aortic elastic properties. The recovery of the renal function allows to initiate the reparative processes leading to at least partial restitution of the structure and features of the aorta, which is called reverse remodelling. Improvement of aortic wall elastic properties after renal transplantation is a continuous and prolonged process.

Arterial pulse wave velocity, inflammatory markers, pathological GH and IGF states, cardiovascular and cerebrovascular disease

Article

Full-text available

Dec 2008
Vasc Health Risk Manag

Michael Graham

Blood pressure (BP) measurements provide information regarding risk factors associated with cardiovascular disease, but only in a specific artery. Arterial stiffness (AS) can be determined by measurement of arterial pulse wave velocity (APWV). Separate from any role as a surrogate marker, AS is an important determinant of pulse pressure, left ventricular function and coronary artery perfusion pressure. Proximal elastic arteries and peripheral muscular arteries respond differently to aging and to medication. Endogenous human growth hormone (hGH), secreted by the anterior pituitary, peaks during early adulthood, declining at 14% per decade. Levels of insulin-like growth factor-I (IGF-I) are at their peak during late adolescence and decline throughout adulthood, mirror imaging GH. Arterial endothelial dysfunction, an accepted cause of increased APWV in GH deficiency (GHD) is reversed by recombinant human (rh) GH therapy, favorably influencing the risk for atherogenesis. APWV is a noninvasive method for measuring atherosclerotic and hypertensive vascular changes increases with age and atherosclerosis leading to increased systolic blood pressure and increased left ventricular hypertrophy. Aerobic exercise training increases arterial compliance and reduces systolic blood pressure. Whole body arterial compliance is lowered in strength-trained individuals. Homocysteine and C-reactive protein are two inflammatory markers directly linked with arterial endothelial dysfunction. Reviews of GH in the somatopause have not been favorable and side effects of treatment have marred its use except in classical GHD. Is it possible that we should be assessing the combined effects of therapy with rhGH and rhIGF-I? Only multiple intervention studies will provide the answer.

РОЛЬ ДИСПЛАЗИИ СОЕДИНИТЕЛЬНОЙ ТКАНИ (НАСЛЕДСТВЕННЫХ НАРУШЕНИЙ СОЕДИНИТЕЛЬНОЙ ТКАНИ) В ИЗМЕНЕНИИ ЭЛАСТИЧЕСКИХ СВОЙСТВ АРТЕРИЙ

Article

Full-text available

Jan 2012

The article reviews the influence of connective tissue dysplasia in the formation of vascular wall rigidity on the basis of literature. Substantiates the importance of studying the role and prospects of connective tissue dysplasia in changing the elastic properties of the arteries in the population.

Molecular Mechanisms of Arterial Stiffening

Article

May 2016

Stiffening of large arteries is a hallmark of vascular aging and one of the most important determinants of the age-related increase in blood pressure and cardiovascular disease events. Despite a substantial genetic component, the molecular mechanisms underlying phenotypic variability in arterial stiffness remain unknown. Previous genetic studies have identified several genetic variants that are associated with measures of arterial stiffness. Here, we review the relevant advances in the identification of pathways underlying arterial stiffness from genomic studies.

Ventricular-vascular coupling - JCM 2014

Data

Full-text available

Feb 2016

Linkage and association mapping for quantitative phenotypes in isolated populations

Thesis

Nov 2011

Christopher Steven Franklin

Many complex diseases are known to have a substantial genetically heritable component. Elucidation of these genetic risk factors provides increased knowledge of the biological mechanisms that result in the diseases while also presenting new potential targets for therapy. This thesis explores the methodology of mapping genetic loci using isolated populations in the context of quantitative trait analysis. Chapter 1 explores the rational for the project, discussing the benefits of using quantitative traits rather than binary disease status and the pros and cons of using isolated populations. This is followed by a brief history of genetic mapping with reference to type 2 diabetes mellitus (T2D) and related quantitative traits. Chapter 2 introduces the methods used in this thesis. This includes strategies to deal with medication, methods to determine kinship between individuals, linkage analysis, association analysis and meta‐analysis of multiple studies. Chapter 3 presents linkage analysis of T2D related traits carried out in 2 – 4 populations depending on availability of the traits and appropriate marker data. Chapter 4 presents the results of association analysis for T2D related traits in 3 – 5 populations using genome‐wide SNP data. The results using the alternate methods described in chapter 2 are compared using fasting glucose as this was the most widely measured phenotype. Chapter 5 introduces additional traits derived by pulse wave analysis and discusses their relevance to metabolic disease before presenting association analysis using the preferred method from chapter 4. An overall discussion of the strengths and weaknesses of the analysis is given in chapter 6.

Erectile dysfunction : a syndrome heralds heart attacks

Article

Full-text available

Feb 2012

The objective of our study is to evaluate degree of endothelial dysfunction and aortic stiffness indices in patients with vasculogenic erectile dysfunction. And to discover a correlation between these findings and coronary artery lesions in their angiographic views. Endothelial dysfunction (ED), in which damage to the lining of the arterial walls impairs the nitric oxide pathway and vasodilation, and is intimately linked to atherogenesis and increased cardiovascular disease (CVD) risk. ED which is due to vasculogenic causes arises from alteration in the release of several vasoactive factors, principally NO, from endothelial cells which is the same pathology to other atherogenic risks. The pathogenesis of both endothelial and erectile dysfunction is intimately linked through decreased expression and activation of endothelial nitric oxide synthase, and production of nitric oxide. So, the pathophysiologic factor underlying both Erectile Dysfunction and cardiovascular disease might be correlated to each other. Many authors agreed that Erectile and endothelial dysfunction are common in individuals with multiple cardiovascular risk factors and are longitudinal predictors of cardiovascular events. This study was carried out in department of cardiology, El-Minia University-Egypt during the period from September 2010 to June 2011. The study included 55 male subjects of mean Age (54±3.2) years. Exclusion criteria includes: (Tobacco smoking, Hypertension, Non vasculogenic cause of erectile dysfunction, Cardiac disease, previous stroke, Diabetes, Obesity and Dyslipidemia) All participants were subjected to (History taking, Clinical Examination, Office blood pressure measurement, Measurement of body mass index, Laboratory investigation (fasting and post-brandial glucose levels, lipogram, blood urea nitrogen and serum creatinine), Echocardiography and a colored duplex ultrasound were done to all participants to test the endothelial functions and Aortic distensibillity indices and Coronary Angiography was done to the patients only to find a lesions in their coronaries and correlates its severity to the parameters of endothelial dysfunction indices. We classified 55 subjects into 2 groups. Group-I (thirty male subjects, aged 52.4±3.8 years old), which are proved to have vasculogenic ED. Group-II (twenty five healthy male subjects, aged 53.04±3.2 years old, used as a control group). Furthermore, Coronary angiography was done to the group-I and correlation was made between their data and severity of coronary lesions in their angiographic projections. The results of this study showed that FMD (reactive hyperemia response) was significantly decreased in the ED group compared with the control group (4.08±1.7% vs 10.4±1.4%, P <0.001) indicating impaired vascular response to reactive hyperemia in patients with ED. Non endothelial vasodilation (GTN dilation%) was lower but statistically insignificant in patients with ED than in control subjects (13.8±2.1% vs 14.4±2.2%, P =0.32 not significant). The relationship between ED and FMD was significant (r=0.87, P< 0.001) whereas no relationship was found between ED and NDD (r =0.13, P <0.32). The SBP, DBP, PP and AoD did not differ significantly between groups (Table 3). Aortic strain (3.3±0.95% vs 10.09±2.2%, P<0.001) and distensibility (1.9±0.64 vs 4.7±1.1 cm2 × dyne-1 ×10-6, P <0.001) were found significantly lower in the ED group than in the control group while Aortic stiffness index (3.9±0.51 vs 2.8±0.2, p<0.001) was found significantly higher in the ED group than in the control group. The relationship between ED and aortic stiffness was also significant (for aortic strain, r=0.81, P <0.001; for aortic distensibility, r=0.78, P <0.001; and for ASI, r= -0.76, p<0.001) . Coronary lesions were detected in 18 out of 30 patients with ED in group-I and normal in 12 patients. The resultant lesions severity is of Mean±SD (44±7.8%) and a strong correlation was found between different endothelial dysfunction and Ao stiffness indices. The study proved that, there's a strong relation between vasculogenic ED and coronary artery affection regardless of presence or absence of cardiac symptoms dictating that, attention must be directed to those individuals with ED complaints aiming to early discover a hidden cardiac risks.

Ventricular-vascular coupling in hypertension: Methodological considerations and clinical implications

Article

Full-text available

Jul 2014

The present review is addressed to analyse the complex interplay between left ventricle and arterial tree in hypertension. The different methodological approaches to the analysis of ventricular vascular coupling in the time and frequency domain are discussed. Moreover, the role of hypertension-related changes of arterial structure and function (stiffness and wave reflection) on arterial load and how ventricular-vascular coupling modulates the process of left ventricular adaptation to hypertension are analysed.The different interplay between vascular bed and left ventricle emerges as the pathophysiological basis for the development of the multiple patterns of ventricular structural adaptation in hypertension and provides a pathway for the interpretation of systolic and diastolic functional abnormalities observed in hypertensive patients. Targeting the therapeutic approach to improve ventricular-vascular coupling may have relevant impact on reversing left ventricular hypertrophy and improving systolic and diastolic dysfunction.

Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci

Article

Feb 2014
AM J HUM GENET

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.

Mechanics and Function of the Pulmonary Vasculature: Implications for Pulmonary Vascular Disease and Right Ventricular Function

Article

Full-text available

Jan 2012

The relationship between cardiac function and the afterload against which the heart muscle must work to circulate blood throughout the pulmonary circulation is defined by a complex interaction between many coupled system parameters. These parameters range broadly and incorporate system effects originating primarily from three distinct locations: input power from the heart, hydraulic impedance from the large conduit pulmonary arteries, and hydraulic resistance from the more distal microcirculation. These organ systems are not independent, but rather, form a coupled system in which a change to any individual parameter affects all other system parameters. The result is a highly nonlinear system which requires not only detailed study of each specific component and the effect of disease on their specific function, but also requires study of the interconnected relationship between the microcirculation, the conduit arteries, and the heart in response to age and disease. Here, we investigate systems-level changes associated with pulmonary hypertensive disease progression in an effort to better understand this coupled relationship.

Common Genetic Variation in the 3 '-BCL11B Gene Desert Is Associated With Carotid-Femoral Pulse Wave Velocity and Excess Cardiovascular Disease Risk The AortaGen Consortium

Article

Nov 2011

Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3'-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency=0.42, β=-0.075±0.012 SD/allele, P=2.8×10(-10); replication β=-0.086±0.020 SD/allele, P=1.4×10(-6)). Combined results for rs7152623 from 11 cohorts gave β=-0.076±0.010 SD/allele, P=3.1×10(-15). The association persisted when adjusted for mean arterial pressure (β=-0.060±0.009 SD/allele, P=1.0×10(-11)). Results were consistent in younger (<55 years, 6 cohorts, n=13 914, β=-0.081±0.014 SD/allele, P=2.3×10(-9)) and older (9 cohorts, n=12 026, β=-0.061±0.014 SD/allele, P=9.4×10(-6)) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio=1.05; confidence interval=1.02-1.08; P=0.0013) and heart failure (hazard ratio=1.10, CI=1.03-1.16, P=0.004). Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor 1 or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.

Impact of genomic polymorphism on arterial hypertension after aortic coarctation repair

Article

Aug 2011

Even after repair of aortic coarctation without restenosis there is a high incidence of arterial hypertension. This study was performed to assess the contribution of several inherited gene polymorphisms, which are known to be related to essential hypertension. 122 patients aged 17-72 years, 46 women, and 2-27 years after repair of isolated aortic coarctation without restenosis were investigated. Genomic polymorphism of angiotensin converting enzyme (ACE I/D), angiotensinogen (AGT, c.704C>T), angiotensin II receptor type 1 (AGTR1, c.1166A>C), aldosterone synthase (CYP11B2, c.-344C>T), endothelin 1 (EDN1, EDN1/ex5-c.5665G>T), G protein (GNB3, c.825C>T), G protein-coupled receptor kinase 4 (GRK4, c.679C>T), fibrillin 1 (FBN1, VNTR(TAAA)) and two polymorphisms each of the ß1 adrenoreceptor (ADRB1, c.145G>A and c.1165C>G), ß2 adrenoreceptor (ADRB2, c.46A>G and c.79C>G), and endothelial NO synthase (NOS3, intron 4 I/D and NOS3, c.894G>T) were determined by PCR amplification and fragment length analysis. Patients were classified "normotensive", if they were not on antihypertensive drugs and showed normal blood pressure both on ambulatory measurement and exercise test. None of the investigated genomic polymorphism could be related to hypertension. Only patients with the ACE I/I genotype had a less pronounced nocturnal dipping and patients with a ADRB1 c.1165 C/C genotype had a higher systolic and mean blood pressure at night. Development of late hypertension after aortic coarctation repair could not be related to the investigated genomic polymorphism. The correlation of the ACE I/D and the ADRB1 c.1165C>G polymorphism to nocturnal dipping and blood pressure at nighttime needs further confirmation.

Aortic stiffness in patients with childhood essential hypertension: Is obesity a risk factor or not?

Article

Aug 2023
Progr Pediatr Cardiol

Circulating Fibrillin Fragment Concentrations in Patients with and without Aortic Pathology

Article

Full-text available

Oct 2022

Objective Fragments of fibrillin-1 and fibrillin-2 are detectable in the plasma of patients with aortic dissections and aneurysms. We sought to determine if plasma fibrillin fragment levels (PFFLs) differ between patients with thoracic aortic pathology and those presenting with non-aortic chest pain. Methods PFFLs were measured in patients with thoracic aortic aneurysm (n=27) or dissection (n=28). For comparison, patients, without aortic pathology, presenting to the emergency department with acute chest pain (n=281) were categorized into groups based on the cause of chest pain: group 1, ischemic cardiac chest pain; group 2, non-ischemic cardiac chest pain; group 3, noncardiac chest pain. PFFLs were measured using a sandwich enzyme-linked immunosorbent assay (ELISA). Results Fibrillin-1 PFFLs were detectable in all patients. Fibrillin-1 PFFLs were lowest in the ischemic cardiac chest pain group. Age, sex and hypertension were associated with differences in fibrillin-1 fragment levels. Fibrillin-2 fragments were more commonly detectable in the thoracic aneurysm and dissection groups compared to the Emergency Department chest pain group (P<0.0001). Patients with aortic dissection demonstrated a trend toward increased detectability (p=0.051) and concentration (p=0.06) of fibrillin-2 fragments compared to patients with aortic aneurysms. Analysis of specific antibody pairs identified fibrillin- 1 B15-HRP26 and fibrillin-2 B205-HRP143 as the most informative in distinguishing between the ED and aortic pathology groups. Conclusions Patients with thoracic aortic dissections demonstrate elevated plasma fibrillin-2 fragment levels (B205-HRP143) compared to patients presenting with ischemic or nonischemic cardiac chest pain and increased fibrillin-1 levels (B15-HRP26) compared to patients with ischemic cardiac chest pain. Investigation of fibrillin-1 and fibrillin- 2 fragment generation may lead to diagnostic, therapeutic and prognostic advances for patients with thoracic aortic dissection.

A Review of Vascular Traits and Assessment Techniques, and Their Heritability

Article

Full-text available

Jun 2022

Various tools are available to assess atherosclerosis, arterial stiffening, and endothelial function. They offer utility in the assessment of hypertensive phenotypes, in cardiovascular risk prediction, and as surrogate endpoints in clinical trials. We explore the relative influence of participant genetics, with reference to large-scale genomic studies, population-based cohorts, and candidate gene studies. We find heritability estimates highest for carotid intima-media thickness (CIMT 35–65%), followed by pulse wave velocity as a measure of arterial stiffness (26–43%), and flow mediated dilatation as a surrogate for endothelial function (14–39%); data were lacking for peripheral artery tonometry. We furthermore examine genes and polymorphisms relevant to each technique. We conclude that CIMT and pulse wave velocity dominate the existing evidence base, with fewer published genomic linkages for measures of endothelial function. We finally make recommendations regarding planning and reporting of data relating to vascular assessment techniques, particularly when genomic data are also available, to facilitate integration of these tools into cardiovascular disease research.

Polymorphisms in Cardiovascular Medicine: The Role of Genetic Variants in Disease Diagnosis and Drug Response

Chapter

May 2006

Marfan syndrome as a complex cardiovascular diesease

Article

Jan 2013

The classical Marfan syndrome results from a heterozygous mutation in the fibrillin-1-gene on chromosome 15, that encodes the structure of fibrillin and the elastic fibers. As MFS has a "variable expression", not everyone has the same symptoms to the same degree and the clinical picture varies from patient to patients During their life about 90% of the patients develop a cardiovascular involvement which determines the survival. Beside the aortic aneurysm the mitral valve prolaps with consecutive mitral regurgitation represents the most frequent cardiovascular symptom. In children frequently a tricuspid prolaps is seen. Independent of valvular pathologies a most often subclinical cardiomyopathy with impaired biventricular impairement can develop. In addition, the diagnosis and treatment of malignant arrhythmias becomes increasingly relevant, as they are probably responsible for sudden cardiac death. Sleep apnea, either obstructive or central, is commonly observed and might have adverse effects on aortic dilatation. Most important is the formation of an aortic aneurysm with aortic rupture and dissection. The speed of progression cannot be predicted precisely. Due to progressive aortic dilatation an aortic regurgitation can develop. Betablockers are established as standard medical prophylaxis. Newer treatment includes angiotensin receptor 1 antagonists, angiotensin converting enzyme inhibitors and sometimes calcium channel blockers. A preventive aortic replacement of dilated parts of the aorta should be performed depending on the degree of aortic dilatation, considering the age and height of the patient, rapidity of progression of the dilatation and family history for dissection.

Influence of genetic factors on early hypertensive complications

Article

Jan 2011

Hypertension is the most prevalent risk factor for cardiovascular disease (CVD), the leading cause of death worldwide, especially in developed countries. Genetic and environmental determinants play important roles in hypertension and its complications. This publication gives a short introduction to the pathogenesis of CVD and summarizes the current findings of the genetic factors involved. This review focuses on a better understanding of the role of candidate genes polymorphisms that play a crucial role in blood pressure regulation, hemostatic processes, oxidative stress and inflammatory responses leading to endothelial damage, and as a result, to vascular remodeling and microalbuminuria. Those gene variants could contribute to inter-individual differences in susceptibility to and outcome of essential hypertension. Therefore, the major challenge in cardiovascular medicine is to find a way of predicting the risk of hypertension complications by genetic markers that, used with imaging techniques, could lead to the development of new and better diagnostic and therapeutic methods.

Systemic Circulation

Article

Dec 2010

Yiu-Fai Cheung

Aging of the Vasculature and Related Systems

Chapter

Jan 2008

Association of Cross-Sectional and Longitudinal Change in Arterial Stiffness With Gene Expression in the Twins UK Cohort

Article

Nov 2015
Hypertension

We investigated whether expression of genes previously implicated in arterial stiffening associates with cross-sectional and longitudinal measures of arterial stiffness. Women from the Twins UK cohort (n=470, aged 39-81 years) had gene expression in lymphoblastoid cell lines measured using an Illumina microarray. Arterial stiffness was measured by carotid-femoral pulse wave velocity and carotid distensibility. A subsample (n=121) of women had repeat vascular measures after a mean±SD follow-up of 4.3±1.4 years. Associations of arterial phenotypes with gene expression levels were examined for 52 genes identified from previous association studies. The gene transcript most closely associated with pulse wave velocity in cross-sectional analysis was ectonucleotide pyrophosphatase/phosphodiesterase (P=0.012). Pleiotropic genetic effects accounted for 14% of the phenotypic correlation between ectonucleotide pyrophosphatase/phosphodiesterase expression and pulse wave velocity. Progression of pulse wave velocity during the follow-up period best related to expression of ectonucleotide pyrophosphatase/phosphodiesterase (β=0.19, P=0.008) and collagen type IV α 1 (β=0.32, P<0.0001). Gene transcripts most closely related to change in carotid distensibility during the follow-up period were endothelial nitric oxide synthase (β=-0.20, P=0.005), angiotensin-converting enzyme (β=-0.15, P=0.035), and B-cell CLL/lymphoma11B (β=0.18, P=0.010). Expression levels of angiotensin-converting enzyme also related to progression in carotid diameter (β=0.21, P=0.012). Expression levels of ectonucleotide pyrophosphatase/phosphodiesterase, involved in arterial calcification, and collagen type IV α 1, involved in collagen formation, correlate with aortic stiffening. These genes may be functional mediators of arterial stiffening.

Genetic Determinants of Arterial Stiffness

Article

Dec 2014

Stiffness of large arteries (called arteriosclerosis) is an independent predictor of cardiovascular morbidity and mortality. Although previous studies have shown that arterial stiffness is moderately heritable, genetic factors contributing to arterial stiffness are largely unknown. In this paper, we reviewed the available literature on genetic variants that are potentially related to arterial stiffness. Most variants have shown mixed depictions of their association with arterial stiffness across multiple studies. Various methods to measure arterial stiffness at different arterial sites can contribute to these inconsistent results. In addition, studies in patient populations with hypertension or atherosclerosis may overestimate the impact of genetic variants on arterial stiffness. Future studies are recommended to standardize current measures of arterial stiffness in different age groups. Studies conducted in normal healthy subjects may also provide better opportunities to find novel genetic variants of arterial stiffness.

Difference of Systemic Vascular Compliance According to the Severity of Coronary Artery Disease in Ischemic Heart Disease

Article

Full-text available

Jan 2003

Background and Objectives：It is contradictory that arterial stiffness, especially in a systemic vascular tree, is related to coronary artery disease. This study was performed to establish the relationship between systemic vascular compliance and the severity of coronary artery disease. Subjects and Methods：The study population was comprised of 53 chronic stable angina patients and 45 normal healthy controls. Coronary angiography was used to determine the involved vessels. The systemic vascular compliance and other hemodynamic variables were measured by a non-invasive pulse dynamic waveform analysis. Results：In the patient group, 15 (24.5%) had one-vessel disease, 15 (24.5%) a two-vessel disease and the remaining 23 (43%) had a three-vessel disease. In the patients with a three-vessel disease, the systemic vascular compliance was significantly lower than those of the other two groups (p<0.05). The systemic vascular compliance of the patients with multi-vessel diseases (including two-vessel and three-vessel) was also significantly lower than that of the controls or patients with a one-vessel disease (p<0.05). The systemic vascular compliance was found to have a significant negative association with the severity of coronary artery disease (Spearman's rho=-0.296, p<0.05). Conclusion：This study has shown that arterial stiffness (or systemic vascular compliance) is significantly associated with the severity coronary artery disease, and the serial non-invasive measurement of the systemic vascular compliance may be useful in the early detection of severe coronary artery disease. (Korean Circulation J 2003 ; 33 (5) : 393-400) KEY WORDS：Compliance；Pulse；Coronary angiography.

Role of Elastic Fibers on Cardiovascular Disease

Article

Full-text available

Dec 2011

Hiroshi Wachi

An important factor in the transition from an open to a closed circulatory system was a change in vessel wall that are dynamic structure composed of cells and extracellular matrix. The component of arterial wall in vertebrates that accounts for these properties is the elastic fiber network organized by medial smooth muscle cells. Elastin and elastin associated protein are synthesized and secreted by vascular smooth muscle cells and are the major extracellular matrix component deposited in the vascular wall. Pathological states related to hypertension or atherosclerosis is associated with vascular wall remodeling, which is deleterious for cardiovascular function. Elastic fiber may be key factors in the pathophysiology of hypertensive or atherosclerotic vascular remodeling. The well-known effects of cardiovascular disease on the deterioration and the promoted degradation of elastic fiber result to loss of arterial wall resilience. Recently, several studies have highlighted new roles for individual components of elastic fiber and their degraded products. This review describes current knowledge regarding components of elastic fibers and discusses relationship between their structural abnormalities and cardiovascular diseases.

Increased carotid plaque burden in men with the fibrillin-1 2/3 genotype

Article

May 2014
CLIN EXP PHARMACOL P

Fibrillin-1 is an important constituent of the vascular wall and earlier studies have indicated an effect of the Fibrillin-1 (FBN1) 2/3 genotype on blood pressure as well as aortic stiffness in men. The aim was to determine if the FBN1 2/3 genotype was associated with presence of carotid plaque and incident cardiovascular morbidity and mortality in middle-aged subjects. The FBN1 genotype was characterized in 5765 subjects (2424 men, 3341 women; aged 45-69 years) recruited from the Malmö Diet and Cancer Study Cardiovascular Cohort, Sweden. Plaque occurrence and intima media thickness (IMT) of the carotid artery were assessed by ultrasound. Incidence of first cardiovascular events (myocardial infarction and stroke) and cause-specific mortality was monitored during a mean of 13.2 years follow-up. The most common FBN1 genotypes were 2/2, 2/3 and 2/4 which accounted for 92.2% (n=5317) of the subjects. There were no differences between the three genotypes regarding age, blood pressure, glucose, lipids, smoking habits, CCA diameter and IMT in men and women. Presence of plaque in the carotid artery was higher in men with genotype 2/3 as compared to the 2/2 and 2/4 genotypes, (55% vs. 46% and 50%, P=0.007). No similar difference was observed in women. No significant relationship was observed between FBN1 genotypes and incidence of cardio vascular disease or all-cause mortality. The increased prevalence of plaque in the carotid artery of middle-aged men with FBN1 2/3 genotype indicates a pathological arterial wall remodelling with a more pronounced atherosclerotic burden.This article is protected by copyright. All rights reserved.

Thoracic Aortic Aneurysm Frequency and Dissection Are Associated With Fibrillin-1 Fragment Concentrations in Circulation

Article

Sep 2013
CIRC RES

Rationale: Mutations in fibrillin-1 are associated with thoracic aortic aneurysm (TAA) in Marfan syndrome. Genome-wide association studies also implicate fibrillin-1 in sporadic TAA. Fragmentation of the aortic elastic lamellae is characteristic of TAA. Objective: Immunoassays were generated to test whether circulating fragments of fibrillin-1, or other microfibril fragments, are associated with TAA and dissection. Methods and results: Plasma samples were obtained from 1265 patients with aortic aneurysm or dissection and from 125 control subjects. Concentrations of fibrillin-1, fibrillin-2, and fibulin-4 were measured with novel immunoassays. One hundred and seventy-four patients (13%) had aneurysms with only abdominal aortic involvement (abdominal aortic aneurysm), and 1091 (86%) had TAA. Of those with TAA, 300 patients (27%) had chronic dissection and 109 (10%) had acute or subacute dissection. Associations of fragment concentrations with TAA (versus abdominal aortic aneurysm) or with dissection (versus no dissection) were estimated with odds ratios (OR) and 95% confidence intervals (CI) adjusted for age, sex, and smoking. Compared with controls, significantly higher percentages of aneurysm patients had detectable levels of fibrillin fragments. TAA was significantly more common (than abdominal aortic aneurysm) in the highest compared with lowest quartile of fibrillin-1 concentration (OR=2.9; 95% CI, 1.6-5.0). Relative to TAA without dissection, acute or subacute dissection (OR=2.9; 95% CI, 1.6-5.3), but not chronic dissection, was more frequent in the highest compared with lowest quartile of fibrillin-1 concentration. Neither TAA nor dissection was associated with fibrillin-2 or fibulin-4. Conclusions: Circulating fibrillin-1 fragments represent a new potential biomarker for TAA and acute aortic dissection.

Heritability and a Genome-Wide Linkage Scan for Arterial Stiffness Wave Reflection and Mean Arterial Pressure

Article

Full-text available

Vascular compliance and the risk of atherosclerotic events

Article

Full-text available

Jan 2003
ARTERIOSCL THROM VAS

Cardiovascular Aspects of the Marfan Syndrome: A Systematic Review

Chapter

Jul 2011

The Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue caused by mutations of the fibrillin-1 gene, which codes for fibrillin, a major component of the extracellular microfibrils. The mean life expectancy in untreated MFS is 32 years with aortic dissection, aortic rupture or cardiac failure accounting for at least 90 percent of all fatalities. In severely affected patients with neonatal MFS, patients are likely to survive a few months only. According to our literature database analysis aortic dilatation is present in 83 percent, aortic regurgitation in 53 percent, mitral valve prolapse in 57 percent, and mitral valve regurgitation in 31 percent of adult males with classic MFS. We put a special focus on the pathogenesis and natural course of cardiovascular disease in MFS, including complications such as arrhythmia, sudden death, and endocarditis or complications during pregnancy. With optimal management, patients may have an acceptable life quality and almost normal life expectancy.

Vascular Complications of Systemic Sclerosis: A Molecular Perspective

Chapter

Jan 2008

Striking vascular abnormalities are a hallmark feature of all types of systemic sclerosis (SSc). Individuals with the limited cutaneous (lcSSc) subset typically manifest Raynaud’s phenomenon many years before onset of frank scleroderma symptoms. Repeated and prolonged peripheral vasospasm frequently leads to painful digital ischemia, ulceration, and gangrene, which often requires surgery and amputation.1 But vascular disease is known to extend beyond the peripheral circulation, and while its role in overall disease evolution is yet to be fully defined, it is likely that some internal organ complications of SSc may be the result of end-organ vascular injury.2 Indeed, scleroderma renal crisis, often an early feature of diffuse (dc) SSc and frequently a cause of mortality in this group, is thought to have an underlying vascular pathophysiology.3–5 And there is evidence that dysregulated vasomotor tone in the pulmonary circulation causes pulmonary artery hypertension secondary to lcSSc.6–8

Fibrillin-1 genotype and risk of prevalent hypertension: A study in two independent populations

Article

May 2012
Blood Pres

Objective: Mutations in the fibrillin-1 gene are the cause of Marfan syndrome. We wanted to investigate the relationship between a mutation in this gene and risk of prevalent hypertension. Methods: In a cross-sectional study, the effect of a G-A substitution in intron 27 in the fibrillin-1 gene (rs11856553) on risk of prevalent hypertension was studied in two large population-based studies: the Health 2006 study, consisting of 3193 women and men, age 18-69 years, and the MONICA10 study, consisting of 2408 women and men, age 41-72 years. In 1646 MONICA10 participants, blood pressure (BP) was also measured by 24-h ambulatory recordings. Results: Among the 3193 Health 2006 participants 23 had the G-A variant, and among the 2408 MONICA10 participants 18 had the G-A variant. In Health 2006, the odds ratio estimate (95% confidence intervals) for the G-A variant for risk of hypertension, defined as systolic (S) BP ≥ 140 mmHg or diastolic (D) BP ≥ 90 mmHg or on antihypertensive medicine, was 2.67 (1.14-6.18), p = 0.022. The corresponding figure for moderate to severe hypertension, defined as SBP ≥ 160 mmHg or DBP ≥ 100 mmHg, was 9.68 (4.24-22.12), p < 0.0001. In MONICA10, the odds ratio estimate (95% confidence intervals) for the G-A variant for risk of moderate to severe ambulatory hypertension, defined as 24-h mean SBP ≥ 150 mmHg or 24-h mean DBP ≥ 90 mmHg, was 5.73 (1.96-16.7), p = 0.0014. Conclusion: The G-A substitution in the fibrillin-1 gene (rs11856553) is a rare genetic variant that is associated with an increased risk of prevalent hypertension, particularly of moderate to severe prevalent hypertension.

Novel Biomarkers Assessing the Calcium Deposition in Coronary Artery Disease

Article

Feb 2012
CURR MED CHEM

Coronary atherosclerosis is the pathophysiologic background of coronary artery disease. Vascular calcification is an actively regulated form of calcified tissue metabolism and a common feature of coronary atherosclerotic plaques. Interestingly, systematic research has revealed that vascular mineralization, is also a strong and independent predictor of cardiovascular morbidity and mortality. Recently, several biomarkers, including osteopontin, fetuin-A, matrix-carboxyglutamic acid protein, pyrophosphates, bone morphogenetic proteins, leptin, osteoprotegerin have emerged as surrogate markers of coronary calcification. Furthermore, biomarkers of vascular calcification can be used as prognostic markers of coronary artery disease and can predict future cardiovascular events and mortality. Nevertheless, there is little knowledge on the usefulness of these biomarkers in evaluating the results of treatments targeting coronary artery disease. Within this context, the present review sets out to discuss the role of new biomarkers assessing calcium deposition in coronary arteries and their role in the prognosis, progression, and treatment of cardiovascular disease.

Implications of Vascular Aging

Article

May 2011

Chronological age is a well-established risk factor for the development of cardiovascular diseases. The changes that accumulate in the vasculature with age, however, are highly variable. It is now increasingly recognized that indices of vascular health are more reliable than age per se in predicting adverse cardiovascular outcomes. The variation in the accrual of these age-related vascular changes is a function of multiple genetic and environmental factors. In this review, we highlight some of the pathophysiological mechanisms that characterize the vascular aging phenotype. Furthermore, we provide an overview of the key outcome studies that address the value of these vascular health indices in general and discuss potential effects on perioperative cardiovascular outcomes.

Genetic Markers of Vascular Aging

Article

Oct 2007
BIOMARK MED

Age is a powerful determinant of cardiovascular risk, being associated with a number of deleterious changes in the cardiovascular system. Increased arterial stiffness is an almost ubiquitous accompaniment of aging. However, there is significant variability in age-related arterial changes between individuals likely due, in part, to genetic factors. Measures of arterial stiffness such as pulse pressure and aortic pulse wave velocity have been shown to be heritable, indicating that genetic factors play a role in the interindividual variation of these phenotypes. Linkage analyses in related individuals have identified several genomic regions that may influence measures of arterial stiffness, and numerous association studies have investigated whether polymorphisms in candidate genes are related to this phenotype. Genome-wide association studies using 500,000 single nucleotide polymorphisms or more are now feasible and will accelerate the discovery of specific genetic polymorphisms that influence vascular aging/stiffness. Such findings will facilitate the development of novel therapies to retard vascular aging.

Cardiovascular characteristics in Marfan syndrome and their relation to the genotype

Article

Full-text available

Jan 2009

Julie De Backer

Marfan syndrome (MFS) is a systemic disorder of connective tissue with autosomal dominant inheritance. The diagnosis of MFS is based on the identification of a combination of clinical manifestations in the ocular, musculoskeletal, and cardiovascular organ systems defined in the Ghent Nosology (De Paepe et al, 1996). Confirmation of the diagnosis in an individual requires the presence of major clinical manifestations in at least two organ systems associated with involvement of a third organ system. In relatives of an affected proband, major involvement of one organ system and involvement of a second organ system confirms the diagnosis. Major clinical criteria are very specific for MFS and include a combination of (4 out of 8) skeletal manifestations, ectopia lentis, dural ectasia and dilatation or dissection of the ascending aorta. The prevalence of- and the guidelines for the assessment of each of these major criteria are well established. Minor clinical criteria are less typical, but their importance in the diagnostic process should not be underestimated. Unfortunately, figures on the prevalence as well as practical guidelines for the assessment of most minor criteria are lacking, especially for those involving the cardiovascular system. The major cardiovascular manifestation in MFS is a progressive dilatation of the ascending aorta, leading to aortic aneurysm formation and eventually to fatal aortic rupture or dissection. Aortic dissection in early adult life is the leading cause of death in MFS. Early diagnosis of individuals at risk of the disease is extremely important as timely treatment of cardiovascular complications has greatly improved life expectancy in MFS. Despite progress in medical and surgical treatment of aortic aneurysms, MFS continues to be associated with significant morbidity and mortality. This may be related to inadequate diagnosis or treatment, but also to the occurrence of cardiovascular problems in ageing MFS patients that were unrecognised until now, such as left ventricular (LV) dysfunction.This thesis is focused on the study of cardiovascular manifestations of MFS which localize beyond the aortic root and on the presently unknown relationship between the severity of the cardiovascular phenotype and the genotype. In the first part, we have studied the prevalence and diagnostic value of the following cardiovascular manifestations of MFS: mitral valve prolapse (MVP) and calcification of the mitral valve annulus, dilatation of the main pulmonary artery (MPA) and dilatation or dissection of the descending aorta. We found a significantly higher prevalence of MVP in MFS patients compared to normal controls, indicating that this feature is useful in the diagnostic evaluation of the condition. In contrast, calcification of the mitral valve annulus appears to be very uncommon, difficult to quantify and therefore not useful in the diagnosis of MFS. We also studied the dimension of the MPA in a series of MFS patients and defined a cut-of value that can be used in the diagnostic evaluation of adult MFS patients. In addition, we showed that diameters of the aorta measured at different levels beyond the aortic root are increased in MFS patients compared to controls. Unfortunately, there was too much overlap with the values obtained in the normal control population to provide cut-off values for the descending aorta. Based on these findings, we developed practical guidelines for the cardiovascular evaluation of patients referred for MFS. In the second part, we studied LV function in MFS patients free of valvular heart disease using a combination of echocardiography (both conventional echocardiography and tissue Doppler imaging) and Magnetic Resonance Imaging. We could demonstrate that MFS patients present a combination of systolic and diastolic dysfunction that is not related to valvular heart disease. This may be attributed to a primary contractile dysfunction of the myocardium and is likely related to the underlying alterations in the elastic features of the myocardium, resulting from the microfibrillar defect. This observation is important in the development of new therapeutic strategies for MFS. Affected individuals may benefit from a treatment with agents that support myocardial function such as angiotensin converting enzyme--inhibitors or angiotensin II type-1 receptor blockers. Furthermore, since MFS patients survive longer thanks to improved medical and surgical treatments, LV dysfunction may become an important issue in the follow-up of these patients. In the third part, we have studied aspects of local and global wave reflection in the aorta of MFS patients. Early return of reflected waves boosts systolic pressure and presents an extra load for the heart and the central vessels. As such, these wave reflections are regarded as one of the important determinants of central blood pressure and can contribute to the development of aortic dilatation in MFS. However, we were unable to demonstrate clear differences in both local and global parameters of wave reflection between MFS patients and normal controls. This could be explained by the fact that increased length of the aorta on the one hand and increased aortic stiffness on the other hand counterbalance each other in MFS patients without yielding any net effect on wave reflection. In the last part of this thesis, we investigated the correlation between the severity of the cardiovascular phenotype in MFS and the type of FBN1 mutation. First, we investigated the correlation between parameters of aortic stiffness (distensibility and pulse wave velocity measured by Magnetic Resonance Imaging) and the type of FBN1 mutation (missense or in-frame deletions/insertions versus nonsense or out-of-frame deletions/insertions). We could not demonstrate any significant differences between these different mutation types, indicating that the FBN1 genotype is not the sole determinant of aortic stiffness. Second, we provided a detailed description of clinical findings in three unrelated MFS families in which an FBN1 mutation was identified and which demonstrate striking intrafamilial phenotypic variability as another illustration of the absence of genotype/phenotype correlations in MFS. This study also illustrated several important issues in MFS. First, repeated clinical examination of suspected patients can be necessary in order to establish a correct and final diagnosis. Second, extensive family history taking and clinical examination of first degree relatives can be highly contributory to the diagnosis. Third, patients with an 'atypical' MFS phenotype may show substantial clinical overlap with other connective tissue disorders such as Weill-Marchesani syndrome or Ehlers-Danlos syndrome and represent a diagnostic challenge. We demonstrated that additional mutational analysis of the FBN1 gene can be a valuable aid to the diagnosis and help to outline medical management options in these challenging cases. In conclusion, we have refined diagnostic guidelines for the assessment of minor cardiovascular manifestations in MFS, shown that LV dysfunction is part of the cardiovascular spectrum and should be followed in the management of MFS patients, and demonstrated that aortic wave reflection is not elevated in MFS. In this work, we also investigated genotype/phenotype correlations, illustrated the marked (intrafamilial) variability in phenotypic expression of the condition, and the value of molecular testing in the diagnosis of MFS. Overall, this thesis nicely illustrates that close interaction and collaboration between cardiology and genetics is an added value to the study of disease pathogenesis of MFS and aortic aneurysms in general.

COL4A1 Is Associated With Arterial Stiffness by Genome-Wide Association Scan

Article

Apr 2009

Pulse wave velocity (PWV), a noninvasive index of central arterial stiffness, is a potent predictor of cardiovascular mortality and morbidity. Heritability and linkage studies have pointed toward a genetic component affecting PWV. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with PWV. The study cohort included participants from the SardiNIA study for whom PWV measures were available. Genotyping was performed in 4221 individuals, using either the Affymetrix 500K or the Affymetrix 10K mapping array sets (with imputation of the missing genotypes). Associations with PWV were evaluated using an additive genetic model that included age, age(2), and sex as covariates. The findings were tested for replication in an independent internal Sardinian cohort of 1828 individuals, using a custom chip designed to include the top 43 nonredundant SNPs associated with PWV. Of the loci that were tested for association with PWV, the nonsynonymous SNP rs3742207 in the COL4A1 gene on chromosome 13 and SNP rs1495448 in the MAGI1 gene on chromosome 3 were successfully replicated (P=7.08 x 10(-7) and P=1.06 x 10(-5), respectively, for the combined analyses). The association between rs3742207 and PWV was also successfully replicated (P=0.02) in an independent population, the Old-Order Amish, leading to an overall P=5.16 x 10(-8). A genome-wide association study identified a SNP in the COL4A1 gene that was significantly associated with PWV in 2 populations. Collagen type 4 is the major structural component of basement membranes, suggesting that previously unrecognized cell-matrix interactions may exert an important role in regulating arterial stiffness.

Impaired Fibrillin-1 Function Promotes Features of Plaque Instability in Apolipoprotein E-Deficient Mice

Article

Nov 2009
CIRCULATION

Arterial stiffness has been associated with an increased cardiovascular risk. The aim of this study was to investigate the interaction between arterial stiffness and atherosclerosis. Mice with a mutation C1039G+/-) in the fibrillin-1 gene leading to fragmentation of the elastic fibers were crossbred with apolipoprotein E-deficient (ApoE-/-) mice. Subsequently, ApoE-/- and ApoE-/-C1039G+/- mice were fed a Western-type diet for 10 or 20 weeks. Our results show that the interaction between arterial stiffness and atherosclerosis is bidirectional. On the one hand, arterial stiffness in ApoE-/-C1039G+/- mice increased more rapidly in the presence of atherosclerotic plaques. On the other hand, arterial stiffness promoted the development of larger and more unstable plaques in ApoE-/-C1039G+/- mice. The plaque area at the aortic root was increased 1.5- and 2.1-fold in ApoE-/-C1039G+/- mice after 10 and 20 weeks of Western-type diet, respectively. After 10 weeks of Western-type diet, plaques of ApoE-/-C1039G+/- mice showed increased apoptosis of smooth muscle cells, which was associated with a decrease in collagen content, an enlargement of the necrotic core, and an increase in macrophages. After 20 weeks of Western-type diet, the number of buried fibrous caps was increased in atherosclerotic lesions of ApoE-/-C1039G+/- mice, not only at the level of the aortic valves but also in the brachiocephalic artery and in the upper, middle, and lower thoracic aorta. Furthermore, acute plaque rupture was observed. These results indicate that fragmentation of the elastic fibers leads to increased vascular stiffness, which promotes features of multifocal plaque instability.

Changes in Endothelial Dysfunction and Associated Cardiovascular Disease Morbidity Markers in GH-IGF Axis Pathology

Article

Dec 2009

Arterial endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and predisposes individuals to the deposition of unstable atherosclerotic plaques. It can also lead to increased arterial stiffness, which is an accepted cause of increased arterial pulse wave velocity (APWV). Endothelial dysfunction is reversed by recombinant human growth hormone (rhGH) therapy in patients with growth hormone (GH) deficiency (GHD), favorably influencing the risk for atherogenesis. Endogenous human growth hormone (hGH), secreted by the anterior pituitary, and levels of insulin-like growth factor-I (IGF-I), produced in response to hGH stimulation of the liver, peak during early adulthood, but decline throughout adulthood. It is suspected that low-grade inflammatory cardiovascular pathophysiologic markers such as homocysteine, nitric oxide, C-reactive protein (CRP), and fibrinogen and plasminogen activator inhibitor along with changes in lipid and glucose metabolism may all contribute to GHD-associated metabolic and cardiovascular complications. These effects are associated with increased APWV, but are attenuated by rhGH therapy in GHD. GH replacement increases IGF-I levels and reduces CRP and large-artery stiffness. Reviews of rhGH in the somatopause have not been overtly favorable. Whereas reviews of rhGH/rhIGF-I combinations in GH resistance are more positive than those for rhGH alone, their combined use in the somatopause is limited. Senescent individuals may benefit from such a combination.

Peripheral Arterial Stiffness and Endothelial Dysfunction in Idiopathic and Scleroderma Associated Pulmonary Arterial Hypertension

Article

Full-text available

Apr 2009

Pulmonary endothelial dysfunction and increased reflection of pulmonary pressure waves have been reported in pulmonary arterial hypertension (PAH). However, the systemic vascular involvement is not fully understood. Our study focused on the systemic arterial stiffness and endothelial involvement in idiopathic and scleroderma associated PAH. Peripheral arterial stiffness and endothelial function were evaluated in 38 patients with idiopathic (n = 28) and scleroderma associated (n = 10) PAH, and 21 control subjects (13 healthy; 8 with scleroderma and normal pulmonary pressure). All participants underwent clinical and cardiopulmonary evaluation. Arterial stiffness was measured through the fingertip tonometry derived augmentation index (AI), which is the boost increase in the late systolic pressure wave after the initial systolic shoulder. Endothelial function was measured by forearm blood flow dilatation response to brachial artery occlusion by a noninvasive plethysmograph (EndoPAT 2000), which is associated with nitric oxide-dependent vasodilatation and yields a peripheral arterial tone (PAT) ratio. Mean systolic pulmonary pressure was 70.5 +/- 21.6 mm Hg (idiopathic-PAH) and 69.3 +/- 20 mm Hg (scleroderma-PAH). AI was higher in scleroderma patients (10.5% +/- 19.6% in healthy controls, 9.0% +/- 21.5% in idiopathic-PAH, 20.1% +/- 19.1% in scleroderma-PAH, and 24.4% +/- 18.9% in scleroderma-controls; nonsignificant). PAT ratio was significantly lower (p < 0.05) than control values in idiopathic-PAH and scleroderma-PAH (PAT ratio: control 2.20 +/- 0.25; idiopathic 1.84 +/- 0.51; scleroderma 1.66 +/- 0.66). AI was not correlated to endothelial dysfunction. There were no differences between the 2 PAH patient groups in age, body mass index, New York Heart Association classification, or 6-min walk test. Our study shows a trend towards increased arterial stiffness in scleroderma (nonsignificant), and also peripheral endothelial dysfunction in idiopathic-PAH and in scleroderma-PAH. These findings suggest involvement of different vessels in scleroderma-PAH compared to idiopathic-PAH.

A Serotonin Transporter Gene Intron 2 Polymorphic Region, Correlated with Affective Disorders, Has Allele-Dependent Differential Enhancer-Like Properties in the Mouse Embryo

Article

Full-text available

Dec 1999

Polymorphic regions consisting of a variable number of tandem repeats within intron 2 of the gene coding for the serotonin transporter protein 5-HTT have been associated with susceptibility to affective disorders. We have cloned two of these intronic polymorphisms, Stin2.10 and Stin2.12, into an expression vector containing a heterologous minimal promoter and the bacterial LacZ reporter gene. These constructs were then used to produce transgenic mice. In embryonic day 10.5 embryos, both Stin2.10 and Stin2.12 produced consistent β-galactosidase expression in the embryonic midbrain, hindbrain, and spinal cord floor plate. However, we observed that the levels of β-galactosidase expression produced by both the Stin2.10 and Stin2.12 within the rostral hindbrain differed significantly at embryonic day 10.5. Our data suggest that these polymorphic variable number of tandem repeats regions act as transcriptional regulators and have allele-dependent differential enhancer-like properties within an area of the hindbrain where the 5-HTT gene is known to be transcribed at this stage of development.

The Effect of an Intronic Polymorphism on Alcohol Dehydrogenase Expression in Drosophila Melanogaster

Article

Full-text available

Nov 1994

Several lines of evidence indicate that natural selection controls the frequencies of an allozyme polymorphism at the alcohol dehydrogenase (Adh) locus in Drosophila melanogaster. However, because of associations among sequence polymorphisms in the Adh region, it is not clear whether selection acts directly (or solely) on the allozymic site. This problem has been approached by using in vitro mutagenesis to distinguish among the effects on Adh expression of individual polymorphisms. This study shows that a polymorphism within the first Adh intron (delta 1) has a significant effect on the level of ADH protein. Like the allozyme, delta 1 shows a geographic cline in frequency, indicating that it may also be a target of natural selection. These results suggest that multisite selection models may be required to understand the evolutionary dynamics of individual loci.

An association between arterial pulse pressure and variation in the fibrillin-1 gene

Article

Full-text available

Nov 1997

To investigate whether variation in the fibrillin-1 gene was associated with blood pressure in healthy middle aged men, as had been observed in patients with abdominal aortic aneurysm. Middle aged men (n = 245), aged 50 to 61 years, were recruited from one of the nine general practices participating in the second Northwick Park heart study. Blood samples were obtained for the preparation of genomic DNA and analysis of plasma variables. Systolic, diastolic, and pulse pressures; fibrillin-1 genotype characterised with a four allele variable tandem nucleotide repeat polymorphism in intron 28. In healthy middle aged men only three common genotypes were observed: 2-2 (frequency 54.1%), 2-3 (16%) and 2-4 (15%). The mean arterial systolic (and pulse) pressure varied according to fibrillin-1 genotype: 2-4 genotype, 126-3 (47.6) mm Hg; 2-2 genotype, 131.0 (51.3) mm Hg; and 2-3 genotype, 135.5 (54.2) mm Hg. The median pulse pressure was 50 mm Hg. Distribution of men around the median pulse pressure, according to genotype, showed a significant trend for patients of 2-4 genotype to have the lowest pulse pressures, those of 2-2 genotype to have intermediate pressures, and those of 2-3 genotype to have the highest pulse pressures (p = 0.003 for healthy men). There appears to be a significant association between fibrillin-1 genotype and arterial pulse pressure in men aged 50 to 61 years.

Relation Between Coronary Artery Disease, Aortic Stiffness, and Left Ventricular Structure in a Population Sample

Article

Full-text available

Oct 1998

To elucidate the relationship between coronary artery disease (CAD), aortic stiffness, and left ventricular structure, we recruited 55 subjects (33 men; average age, 63+/-1 years) with previously unknown CAD from a healthy general population sample, as well as 55 control subjects matched for gender, age, and serum cholesterol level. We measured arterial blood pressure and the systolic expansion of the transverse aorta and left ventricular structure by echocardiography. Aortic stiffness was higher in CAD patients than in controls, with a brachial pulse pressure of 59+/-3 versus 52+/-2 mm Hg and stiffness indices of Ep=212+/-26 versus 123+/-13 kN/m2 and beat=16+/-2 versus 9+/-1 (all P<0.01). Mean arterial pressure was similar in both groups during the measurements (95+/-2 versus 93+/-2 mm Hg, P=NS). Most CAD patients (61%) were in the highest stiffness quartile defined by the normal control values (P<0.05 versus control). Left ventricular mass index was also higher in CAD patients than in matched controls (139+/-5 versus 123+/-4 g/m2, P<0.05). We conclude that aortic stiffness and left ventricular mass are increased in subjects newly diagnosed as having CAD. This might explain previously reported associations of an increased mortality, particularly from CAD, found among subjects with elevated pulse pressures.

Association of ACE gene polymorphism with arterial stiffness in patients with type 2 diabetes

Article

Full-text available

Nov 1999
DIABETES CARE

To assess the relationship between the insertion (I)/deletion (D) polymorphism of the ACE gene and arterial distensibility in patients with type 2 diabetes and healthy control subjects. Aortic and carotid arterial distensibility were evaluated by measuring aortic pulse-wave velocity (a-PWV) and carotid stiffness beta using an echo-tracking system in 137 patients with type 2 diabetes and 260 age-matched control subjects. a-PWV and carotid stiffness beta were significantly higher in patients with type 2 diabetes than in age-matched control subjects (P < 0.05). Both stiffness beta and a-PWV were significantly higher in the patients with the II genotype than in those with the DD genotype (P < 0.001). In the control subjects, multiple regression analysis showed that age and decreased HDL cholesterol were independently associated with increased a-PWV (R2 = 0.244, P < 0.0001) and that age, systolic and diastolic blood pressure, and BMI were independently associated with increased carotid stiffness beta (R2 = 0.454, P < 0.0001). In the patients with type 2 diabetes, age, gene dose of the I allele, and systolic and diastolic blood pressure were independently associated with increased a-PWV (R2 = 0.545, P < 0.0001), and age, gene dose of the I allele, and systolic blood pressure were associated with increases in carotid stiffness beta (R2 = 0.314, P < 0.0001). These results suggested that ACE polymorphism is associated with the impairment of aortic and carotid distensibility in patients with type 2 diabetes.

Mechanical properties of the common carotid artery in Williams syndrome

Article

Full-text available

Sep 2000
HEART

To determine whether arterial wall hypertrophy in elastic arteries was associated with alteration in their mechanical properties in young patients with Williams syndrome. Arterial pressure and intima-media thickness, cross sectional compliance, distensibility, circumferential wall stress, and incremental elastic modulus of the common carotid artery were measured non-invasively in 21 Williams patients (mean (SD) age 8.5 (4) years) and 21 children of similar age. Systolic and diastolic blood pressures were higher in Williams patients (125/66 v 113/60 mm Hg, p < 0.05). The mean (SD) intima-media thickness was increased in Williams patients, at 0.6 (0.07) v 0.5 (0.03) mm (p < 0. 001). Normotensive Williams patients had a lower circumferential wall stress (2.1 (0.5) v 3.0 (0.7) mm Hg, p < 0.01), a higher distensibility (1.1 (0.3) v 0.8 (0.3) mm Hg(-1).10(-2), p < 0.01), similar cross sectional compliance (0.14 (0.04) v 0.15 (0.05) mm(2). mm Hg(-1), p > 0.05), and lower incremental elastic modulus (7.4 (2. 0) v 14.0 (5.0) mm Hg.10(2); p < 0.001). The compliance of the large elastic arteries is not modified in Williams syndrome, even though increased intima-media thickness and lower arterial stiffness are consistent features. Therefore systemic hypertension cannot be attributed to impaired compliance of the arterial tree in this condition.

Large Artery Stiffness: Implications For Exercise Capacity And Cardiovascular Risk

Article

Full-text available

Apr 2002

Bronwyn Kingwell

1. Large artery stiffness, or its inverse, compliance, determines pulse pressure, which, in turn, influences myocardial work capacity and coronary perfusion, both of which impact on exercise capacity and cardiovascular risk. 2. In support of a role for arterial properties in exercise performance, aerobically trained athletes (aged 30–59 years) have lower arterial stiffness than their sedentary counterparts. Furthermore, in healthy older subjects (aged 57–80 years), time to exhaustion on treadmill testing correlated positively with arterial compliance. 3. Arterial stiffness is more closely linked to exercise capacity and myocardial risk in patients with coronary disease where, independently of degree of coronary disease, those with stiffer proximal arteries have a lower exercise-induced ischaemic threshold. 4. Moderate aerobic training elevates resting arterial compliance by approximately 30%, independently of mean pressure reduction, in young healthy individuals but not in isolated systolic hypertensive patients. Rat training studies support a role for exercise training in structural remodelling of the large arteries. 5. High-resistance strength training is associated with stiffer large arteries and higher pulse pressure than matched controls. 6. Large artery stiffness is an important modulator of the myocardial blood supply and demand equation, with significant ramifications for athletic performance and ischaemic threshold in coronary disease patients. Moderate aerobic training, but not high-resistance strength training, reduces large artery stiffness in young individuals whereas older subjects with established isolated systolic hypertension are resistant to such adaptation.

Independent prognostic information provided by sphygmomanometrically determined pulse pressure and mean arterial pressure in patients with left ventricular dysfunction

Article

Jan 1998
CIRCULATION

Genomic organization of the sequence coding for fibrillin, the defective gene product in Marfan Syndrome

Article

Feb 1994

Marfan syndrome results from mutations in an extracellular matrix glycoprotein, fibrillin. Previous studies have characterized ∼6.9-kb of the estimated 10-kb fibrillin transcript. We have now completed the primary structure of fibrillin, elucidated the exon/intron organization of the gene and derived a physical map of the genetic locus. Pre-fibrillin consists of 2,871 amino acids which, excluding the signal peptide, are arranged into five structurally distinct regions. The largest of these regions comprises about 75% of the entire protein and consists of numerous repeated cysteine-rich sequences homologous to the peptide motifs of the epidermal growth factor (EGF) and transforming growth factor-β binding protein (TGF-bp). Forty-three of the forty-six EGF-like repeats contain a calcium binding consensus sequence (EGF-CB) conceivably mediating protein - protein interactions. Fibrillin exhibits a few additional cysteine-rich modules that are apparently unique to this macromolecule and may represent evolutionary variants of the EGF-CB and TGF-bp motifs. Almost all of the cysteine-rich repeats are encoded by single exons; consequently, the fibrillin gene is relatively large (∼110-kb) and highly fragmented (65 exons). This study provides the first comprehensive analysis of the fibrillin gene and relevant information for the full characterization of Marfan syndrome mutations.

In: McDonald's Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles

Book

Jan 2005

Association of fibrillin 1 single-nucleotide polymorphism haplotypes with systemic sclerosis in Choctaw and Japanese populations

Article

Apr 2001

Previously, we demonstrated with the use of microsatellite markers that a 2-cM haplotype on chromosome 15q containing the fibrillin 1 gene (FBN1) was strongly associated with systemic sclerosis (SSc) in the Choctaw, a population with high SSc prevalence. In this study, all 69 known FBN1 exons were sequenced to ascertain the presence of changes that might show associations with SSc in the Choctaw and Japanese SSc patients and controls. Screening of FBN1 exons was accomplished by polymerase chain reaction-based fluorescence sequencing of genomic DNA using single-nucleotide polymorphism (SNP) haplotypes, and their frequencies were determined with a new algorithm that recognizes past recombination events between sites. Haplotype phylogenies were inferred using the median-joining network analysis. Five SNPs were identified in FBN1. They are located in the 5'-untranslated region (SNP-1), exon 15 (SNP-2), intron 17 (SNP-3), exon 27 (SNP-4), and intron 27 (SNP-5). Only SNP-1 (T-->C) demonstrated an association with SSc in the Choctaw. Eleven FBN1 SNP haplotypes were ascertained in the Choctaw population, 2 of which (SNPs 5 and 6) were found only in the SSc patients. These same FBN1 SNP haplotypes were associated with SSc in the Japanese. A SNP in the 5'-untranslated region of FBN1 (SNP-1, C allele) was strongly associated with SSc in the Choctaw. Furthermore, this polymorphism is present on 2 unique FBN1 haplotypes found only in Choctaw SSc patients. The same 2 haplotypes demonstrate associations with SSc in the Japanese. These data extend the earlier microsatellite studies and are consistent with the hypothesis that FBN1 or a nearby gene on chromosome 15q is involved in SSc susceptibility in the Choctaw and the Japanese.

Clustering of mutations associated with mild Marfan‐like phenotypes in the 3′ region of FBN1 suggests a potential genotype–phenotype correlation

Article

Mar 2000
Am J Med Genet

Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome, a dominantly inherited disorder of connective tissue that primarily involves the cardiovascular, ocular, and skeletal systems. There is a remarkable degree of variability both within and between families with Marfan syndrome, and FBN1 mutations have also been found in a range of other related connective tissue disorders collectively termed type-1 fibrillinopathies. FBN1 mutations have been found in almost all of the 65 exons of the FBN1 gene and for the most part have been unique to one affected patient or family. Aside from the “hot spots” for the neonatal Marfan syndrome in exons 24–27 and 31–32, genotype–phenotype correlations have been slow to emerge. Here we present the results of temperature-gradient gel electrophoresis analysis of FBN1 exons 59–65. Six mutations were identified, only one of which had been previously reported. Two of the six mutations were found in patients with mild phenotypes. Taken together with other published reports, our results suggest that a sizable subset (ca. 40%) of mutations in this region is associated with mild phenotypes characterized by the lack of significant aortic pathology, compared with about 7% in the rest of the gene. In two cases, mutations affecting analogous positions within one of the 43 cbEGF modules of FBN1 are associated with mild phenotypes when found in one of the 6 C-terminal modules (encoded by exons 59–63), but are associated with classic or severe phenotypes when found in cbEGF modules elsewhere in the gene. Am. J. Med. Genet. 91:212–221, 2000. © 2000 Wiley-Liss, Inc.

Clustering of fibrillin “FBN1” mutations in Marfan syndrome patients at cysteine residues in EGF-like domains

Article

Jan 1992

The Marfan syndrome is an autosomal dominant heritable disorder of connective tissue with prominent involvement of the ocular, skeletal, and cardiovascular systems. The gene on chromosome 15 encoding fibrillin (FBN1), a 350-kDa glycoprotein component of the extracellular microfibril, is the site of defect in most, if not all cases. Complementary DNA sequence reveals a gene composed largely of epidermal growth factor-like repeats, each containing six predictably spaced cysteine residues. To date, two FBN1 gene missense mutations have been reported. Here we describe the identification of three new missense mutations in the FBN1 gene in patients with the Marfan syndrome. All of the 5 characterized missense mutations occur within the epidermal growth factor-like repeats of the FBN1 gene. In addition, 4 of 5 involve the substitution of cysteine residues and 3 of 5 substitute the third cysteine in the epidermal growth factor-like motif consensus sequence. These data suggest that defined residues within EGF-like domains of FBN1 have particular significance and, when altered, play a pivotal role in expression of the Marfan phenotype.

Effect of reduced aortic compliance on cardiac efficiency and contractile function of in situ canine left ventricle

Article

Oct 1992

This study tests the hypothesis that arterial vascular stiffening adversely influences in situ left ventricular contractile function and energetic efficiency. Ten reflex-blocked anesthetized dogs underwent a bypass operation in which a Dacron graft was sewn to the ascending aorta and connected to the infrarenal abdominal aorta via a plastic conduit. Flow was directed through either native aorta or plastic conduit by placement of vascular clamps. Arterial properties were measured from aortic pressure-flow data, and ventricular function was assessed by pressure-volume (PV) relations. Coronary sinus blood was drained via an extracorporeal circuit for direct measurement of myocardial O2 consumption (MVO2). Data at multiple steady-state preload volumes were combined to derive chamber function and energetics relations. Energetic efficiency was assessed by the inverse slope of the MVO2-PV area relation. Directing flow through plastic versus native aorta resulted in a 60-80% reduction in compliance but little change in mean resistance. Arterial pulse pressure rose from 34 to 99 mm Hg (p less than 0.001). Contractile function assessed by the end-systolic PV relation, stroke work-end-diastolic volume relation, and dP/dtmax at matched end-diastolic volume did not significantly change. However, MVO2 increased by 32% (p less than 0.01) and was matched by a rise in PV area, such that the MVO2-PV area relation and efficiency was unaltered. The MVO2 required to sustain a given stroke volume, however, increased from 20% to 40%, depending on the baseline level (p less than 0.001). Thus, whereas the contractile function and efficiency of normal hearts are not altered by ejection into a stiff vascular system, the energetic cost to the heart for maintaining adequate flow is increased. This suggests a mechanism whereby human vascular stiffening may yield little functional decrement at rest but limit reserve capacity under conditions of increased demand.

Aortic distensibility in patients with isolated hypercholesterolaemia, coronary artery disease, or cardiac transplant

Article

Sep 1991

The stiffness of the thoracic aorta can be assessed non-invasively. If aortic stiffness can be shown to be related to coronary heart disease, perhaps it can be used to identify which patients with hypercholesterolaemia are most likely to have atheromatous changes and thus to be selected for intensive cholesterol-lowering treatment. Hence the distensibility of the transverse aortic arch was measured by echocardiography of the aortic arch in four groups of patients--symptom-free patients with normal serum cholesterol; symptom-free patients with raised serum cholesterol; patients with coronary heart disease (all with raised serum cholesterol), and post-heart-transplant patients. In all groups distensibility fell with age. The regression slope was steeper (p less than 0.05) for patients with known coronary disease than for either of the disease-free groups, and among cardiac transplant recipients there was also a segregation of distensibility values between those with and without atheroma in their native hearts. The results indicate that aortic distensibility might be an indicator of coronary heart disease and that it might be useful in identifying which symptom-free subjects with modest hypercholesterolaemia should be treated aggressively.

Pulsatile versus steady component of blood pressure: A cross-sectional analysis and a prospective analysis on cardiovascular mortality

Article

May 1989

Studies on the prognostic significance of blood pressure on cardiovascular disease have essentially investigated the levels of diastolic or systolic blood pressure. However, blood pressure may also be divided into two other components: steady (mean arterial pressure) and pulsatile (pulse arterial pressure). The relations of these two components with cardiovascular risk factors and cardiovascular mortality were investigated in 18,336 men and 9,351 women aged 40-69 years, who were followed up for a mean period of 9.5 years. However, the interpretation of the relations is complicated by the strong correlation existing between these two components. A principal component analysis was performed to obtain two independent parameters: a steady and a pulsatile component index, strongly correlated with mean and pulse arterial pressure, respectively. In the cross-sectional analysis, relations were stronger with the steady component index than with the pulsatile component index; an association was found between left ventricular hypertrophy and the pulsatile component index in both sexes. The survival analysis was not performed in women under 55 as only 11 cardiovascular deaths occurred in this group. The steady component index was a strong prognostic factor of all types of cardiovascular death in both sexes. In women, the pulsatile component index was positively correlated to death from coronary artery disease and inversely correlated to stroke. In conclusion, the steady component of blood pressure is a strong risk factor for cardiovascular death in both sexes; the pulsatile component could be a risk factor independent of the steady component in women older than 55 years.

Aortic Input Impedance in Normal Man: Relationship to Pressure Wave Forms

Article

Aug 1980

The relationship between the shape of the ascending aortic pressure wave form and aortic input impedance was studied in 18 patients who underwent elective cardiac catheterization but in whom no heart disease was found. Ascending aortic flow velocity and pressure were simultaneously recorded from a multisensor catheter with an electromagnetic velocity probe and a pressure sensor mounted at the same location. Another pressure sensor at the catheter tip provided left ventricular pressure or a second aortic pressure to determine pulse-wave velocity. Fick cardiac outputs were used to scale the velocity signal to instantaneous volumetric flow. Input impedance was calculated from 10 harmonics of aortic pressure and flow. For each patient, impedance moduli and phases from a minimum of 15 beats during a steady state were averaged. Peripheral resistance was 1137 ± 39 dyn-sec-cm-5 (± SEM) and characteristic impedance was 47 ± 4 dyn-sec-cm-5; pulse-wave velocity was 6.68 ± 0.32 m-sec-1. In all patients, a well-defined systolic infection point divided the aortic pressure wave form into an early and late systolic phase. The patients were classified into three groups: group A (n=7) - patients whose late systolic pressure exceeded early systolic pressure; group B (n = 7) - patients whose early and late systolic pressures were nearly equal: group C (n=4) - patients whose early systolic pressure exceeded late systolic pressure. Group A and B patients all demonstrated oscillations of the impedance moduli about the characteristic impedance. Group C patients demonstrated flatter impedance spectra. Thus, a larger secondary rise in pressure was associated with a more oscillatory impedance spectrum. These results suggest that the differences in pressure wave forms are due to differences in reflections in the arterial tree and not secondary to differences in cardiac function. Using pulse-wave velocity, the 'effective' reflection site distance was determined from both pressure (48 cm) and impedance (44 cm) data, implying that the region of the terminal abdominal aorta acts as the major reflection site in normal adult man.

A Gly1127Ser mutation in an EGF-like domain of the Fibrillin-I gene is a risk factor for ascending aortic aneurysm and dissection

Article

Jul 1995

Ascending aortic disease, ranging from mild aortic root enlargement to aneurysm and/or dissection, has been identified in 10 individuals of a kindred, none of whom had classical Marfan syndrome (MFS). Single-strand conformation analysis of the entire fibrillin-1 (FBN1) cDNA of an affected family member revealed a G-to-A transition at nucleotide 3379, predicting a Gly1127Ser substitution. The glycine in this position is highly conserved in EGF-like domains of FBN1 and other proteins. This mutation was present in 9 of 10 affected family members and in 1 young unaffected member but was not found in other unaffected members, in 168 chromosomes from normal controls, and in 188 chromosomes from other individuals with MFS or related phenotypes. FBN1 intragenic marker haplotypes ruled out the possibility that the other allele played a significant role in modulating the phenotype in this family. Pulse-chase studies revealed normal fibrillin synthesis but reduced fibrillin deposition into the extracellular matrix in cultured fibroblasts from a Gly1127Ser carrier. We postulate that the Gly1127Ser FBN1 mutation is responsible for reduced matrix deposition. We suggest that mutations such as this one may disrupt EGF-like domain folding less drastically than do substitutions of cysteine or of other amino acids important for calcium-binding that cause classical MFS. The Gly1127Ser mutation, therefore, produces a mild form of autosomal dominantly inherited weakness of elastic tissue, which predisposes to ascending aortic aneurysm and dissection later in life.

Increase in pulse pressure impair acetylcholine-induced vascular relaxation

Article

Feb 1995
Am J Physiol

Effects of pulse pressure on acetylcholine-induced endothelium-dependent relaxation were investigated using a cascade bioassay model. Intact carotid arteries from rabbits were perfused at constant flow, and activity of endothelium-derived relaxing factor (EDRF) was assayed by measuring changes in isometric tension in a detector ring without endothelium. When pulse pressure of the donor artery was raised from approximately 2 to 10 mmHg, relaxation to acetylcholine (10(-7) M) was reduced from 31 +/- 3 (means +/- SE) to 20 +/- 2% (expressed as percent relaxation of phenylephrine-induced tone). Responses of the detector ring to nitroprusside were unchanged. Superoxide dismutase (SOD) and indomethacin each prevented impairment of relaxation to acetylcholine at high pulse pressure. When the donor artery was perfused at a higher mean pressure, elevation of pulse pressure also impaired relaxation to acetylcholine, and this impairment was prevented by SOD. These findings suggest that elevation of pulse pressure inhibits acetylcholine-induced, endothelium-dependent relaxation, and this inhibitory effect is mediated by generation of oxygen radicals.

Relation between age, arterial distensibility, and aortic dilatation in the Marfan syndrome

Article

Sep 1994
AM J CARDIOL

This study examined the relations between age, arterial distensibility, and systemic hemodynamics in patients with the Marfan syndrome. The study group included 170 patients referred to a specialist clinic, of whom 55 (age 26 +/- 12 years) were diagnosed as having Marfan syndrome. The remaining 115 patients (age 25 +/- 14 years) formed a control group. Each patient underwent echocardiographic examination, with measurement of ascending aorta diameter at end-diastole and end-systole, and aortic flow velocities. The elastic properties of the aorta were indexed by calculation of aortic distensibility, wall stiffness, and systemic pulse wave velocity. Mean end-diastolic aortic diameter in the Marfan group (38 +/- 9 mm) was greater than that in the controls (26 +/- 4 mm, p < 0.01). Resting heart rate and aortic flow velocities were similar in the 2 groups, but systemic arterial pulse pressure was greater in the Marfan group (50 +/- 12 mm Hg) than in the controls (41 +/- 8 mm Hg, p < 0.01). Aortic diameter increased with age in both groups, but at all ages the Marfan group exhibited greater aortic diameters (p < 0.05). Aortic distensibility was less in the Marfan group (2.6 +/- 1.3 cm2.dynes-1 x10(-6)) than in the controls (6.2 +/- 2.1 cm2.dynes-1 x 10(-6), p < 0.01), and the aortic wall stiffness index was greater in the Marfan group (7.9 +/- 3.4) than in the controls (2.8 +/- 0.6, p < 0.01). Aortic wall stiffness increased with age and aortic diameter, but at all ages the Marfan group exhibited a stiffer aorta for a given diameter than did the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise training increases total systemic arterial compliance in humans

Article

Feb 1994
Am J Physiol

Using a noninvasive technique we have investigated the effect of 4 wk of exercise training on total systemic arterial compliance (SAC) in 13 previously sedentary young males. SAC is assessed from simultaneous measurements of ascending aortic blood velocity using Doppler velocimetry and surrogate estimates of aortic root pressure obtained by applanation tonometry of the right carotid artery. Subsequent calibration of the pressure waveform is by linear interpolation against brachial arterial pressures measured sphygmomanometrically. Exercise training increased the overall mean maximum oxygen consumption (VO2 max) by 5.1 ml.min-1 x kg-1 (95% confidence limits 1.30-8.80, P < 0.01) and decreased mean systolic blood pressure by 8.4 mmHg [95% confidence interval (CI) 2.9-13.9, P < 0.01]. Mean SAC increased by 0.26 units (95% CI 0.10-0.43, P < 0.01) with the regional stiffness of the aortic arch (measured echocardiographically using the beta-index) showing a complementary decrease of 1.03 (95% CI -2.25-0.19, P < 0.05). Assuming a logarithmic arterial volume-pressure relationship, we were able to dissociate the change in SAC due to the exercise training-induced decrease in blood pressure from that due to change in the intrinsic compliance of the systemic arteries. Our results indicate that 1) exercise training increases SAC; 2) that the increase in SAC is greater than that due to changes in blood pressure and is likely to include a component due to change in intrinsic arterial compliance; and 3) that the induced change in SAC is linearly related to change in VO2 max.

Coronary circulation in dogs with an experimental decrease in aortic compliance

Article

May 1993
J AM COLL CARDIOL

This study was designed to investigate the effects of decreased aortic compliance on the coronary circulation. A decrease in aortic compliance due to arteriosclerosis is observed in patients with coronary artery disease. However, the effects of decreased aortic compliance on the coronary circulation have not yet been investigated sufficiently. Hemodynamics, subendocardial electrocardiogram (ECG), myocardial segmental length and myocardial blood flow were investigated in six dogs with aortic bandaging (bandaged group) and five dogs with a sham operation (control group) at rest and during pacing 4 weeks after surgery. Aortic compliance in the bandaged group was less than that in the control group (0.24 +/- 0.20 vs. 0.50 +/- 0.22 ml/mm Hg, p < 0.05). Pulse pressure and the tension-time index were significantly greater in the bandaged group than in the control group, but systemic vascular resistance was not altered significantly. The subendocardial/subepicardial flow ratio was lower in the bandaged group than in the control group (0.95 +/- 0.31 vs. 1.57 +/- 0.26, p < 0.05). In the region supplied by the left circumflex artery with a stenosis that was adjusted to eliminate reactive hyperemia, rapid atrial pacing (heart rate 200 beats/min) further decreased endocardial flow and the endocardial/epicardial flow ratio in the bandaged group. Moreover, both the reduction of segmental shortening and the ST elevation on the subendocardial ECG in the left circumflex-supplied region during pacing were greater in the bandaged group. These results indicate that decreased aortic compliance greatly increases the risk of subendocardial ischemia in the presence of coronary stenosis.

Validation of Carotid Artery Tonometry as a Means of Estimating Augmentation Index of Ascending Aortic Pressure

Article

Mar 1996

Our objective was to validate a carotid artery tonometry-derived augmentation index as a means to estimate augmentation index (AI) of ascending aortic pressure under various physiological conditions. A total of 66 patients (50 men, 16 women; mean age, 55 years; range, 21 to 78 years; 44 in Taiwan and 22 in the United States) undergoing diagnostic catheterization were studied. Arterial pressure contours were obtained simultaneously from the right common carotid artery by applanation tonometry with an external micromanometer-tipped probe and from the ascending aorta by a micromanometer-tipped catheter at baseline (n = 62), after handgrip (n = 36), or after sublingual nitroglycerin administration (n = 17). The AI (expressed as percentage values) was calculated as the ratio of amplitude of the pressure wave above its systolic shoulder to the total pulse pressure. The carotid AI was consistently lower than the aortic AI, but the two were highly correlated at baseline and after both handgrip and nitroglycerin. Mean +/- SD and correlation coefficients were baseline (14 +/- 16, 28(+) +/- 17, .77), handgrip (18 +/- 19, 32(+) +/- 15, .86), and nitroglycerin (7 +/- 12, 18(+) +/- 13, .52). In addition, after adjusting for age, sex, height, blood pressure, heart rate, and study site, the changes of both AIs from baseline values with handgrip or nitroglycerin were highly associated such that the aortic AI could be approximated from the carotid AI with appropriate regression equations. The high correlations and predictable changes after interventions between the central AI and those estimated from noninvasive carotid tonometry suggest that this technique may have wide applicability for many cardiovascular studies.

Adverse Influence of Systemic Vascular Stiffening on Cardiac Dysfunction and Adaptation to Acute Coronary Occlusion

Article

Apr 1996

[corrected] Age is an independent risk factor for increased mortality from ischemic heart disease. Arterial stiffening with widening of the pulse pressure may contribute to this risk by exacerbating cardiac dysfunction after total coronary artery occlusion. To test the above hypothesis, 14 open-chest dogs underwent surgery in which the intrathoracic aorta was bypassed with a stiff plastic tube. Directing ventricular outflow through the bypass widened the arterial pulse pressure from 41 to 115 mm Hg at similar mean pressure and flow. Hearts ejecting into the native aorta (NA) exhibited only modest dysfunction after two minutes of mid-left anterior descending coronary artery occlusion. However, the same occlusion applied during ejection into the bypass tube (BT) induced far more severe cardiodepression (ie, systolic pressure fell by -41+/-10 mm Hg for BT versus -15+/-3 mm Hg for NA, and end-systolic volume rose by 15+/-3 versus 6+/-2 mL), with a threefold greater decline in ejection fraction. This disparity was not due to higher baseline work loads because total pressure-volume area was similar in both cases. Furthermore, marked increases in basal work load and wall stress induced by angiotensin II infusion (in four additional studies) did not reproduce this behavior. Although peak systolic chamber stress was greater with the BT, this did not increase systolic dyskinesis as measured in the central ischemic zone. However, the total mass of myocardium that was rendered severely ischemic (ie, flow reduced by > or = 80%) was twice as large with BT ejection, likely expanding the region of dyskinesis. This disparity may relate to altered phasic coronary flow during BT ejection, which displays marked enhancement of systolic flow and renders the heart more vulnerable to diminished mean and systolic perfusion pressures. Cardiac ejection into a stiff systemic vasculature augments cardiac dysfunction and ischemia due to coronary occlusion by tightening the link between cardiac systolic performance and myocardial perfusion. This may contribute to the higher mortality risk from ischemic heart disease due to age.

Influence of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor Gene Polymorphisms on Aortic Stiffness in Normotensive and Hypertensive Patients

Article

Sep 1996

Clinical and experimental studies have demonstrated a major role of the renin-angiotensin system in the functional and structural changes of the large arteries in hypertension. Because genetic studies may help us to understand the mechanisms underlying the involvement of this system in arterial regulation, the present study was designed to assess the contribution of polymorphisms of the ACE insertion/deletion (I/D) and angiotensin II type 1 receptor (AGTR1 A 1166C) genes on aortic stiffness regulation. This study included 311 untreated hypertensive and 128 normotensive subjects. Aortic stiffness was evaluated by measurement of the carotid-femoral pulse-wave velocity (PWV). In normotensive subjects, the two polymorphisms did not influence any of the studied parameters. In hypertensive subjects, there was a decreasing trend of mean PWV with the number of ACE D alleles, but this association became significant only after adjustment for blood pressure (P < .05). Conversely, the AGTR1 A 1166C polymorphism was independently associated with aortic stiffness. Mean values of PWV were 11.6 +/- 2.7 m/s in AGTR1 AA homozygotes, 13.3 +/- 3.3 m/s in AC heterozygotes, and 15.3 +/- 4.3 m/s in CC homozygotes (P < .0001 and P < .00001 after adjustment for age and mean blood pressure, respectively). The percentage of variance of PWV explained by AGTR1 A 1166C polymorphism (11.6%) was much larger than that of ACE I/D polymorphism (1.7%). These results suggest that in hypertensive but not normotensive subjects, the AGTR1 and ACE genotypes are involved in the regulation of aortic rigidity. The presence of the AGTR1 C allele is a strong independent determinant of aortic stiffness, whereas presence of the ACE 1 allele is weakly associated with increased stiffness.

Angiotensin II Type 1 Receptor A/C1166 Polymorphism: Relationships With Blood Pressure and Cardiovascular Structure

Article

Jan 1997

The angiotensin II type 1 (AT1) receptor has a key role in mediating the vasoconstrictor and growth-promoting effects of angiotensin II. It has been reported that a polymorphism of the AT1 receptor gene (an A/C transversion at position 1166) may be associated with cardiovascular phenotypes, such as arterial blood pressure and aortic stiffness, that underlie a condition of increased cardiovascular risk. We examined a sample of 212 subjects randomly selected from a general population in northern Italy to investigate the role of AT1 receptor gene polymorphism, in the regulation of blood pressure and cardiovascular growth. We measured blood pressure (both clinic and 24-hour ambulatory recording), left ventricular mass (echocardiography), and carotid artery wall thickness (B-mode ultrasound); we assessed the AT1 receptor genotype by polymerase chain reaction and allele-specific oligonucleotide hybridization. Blood pressure values were lower in CC homozygotes than in heterozygotes and AA homozygotes; the difference was statistically significant for clinic measurements (mean difference for mean blood pressure, -6.6 mm Hg, P = .01; 95% confidence interval, -1.6 to -11.7 mm Hg) but not for ambulatory blood pressure measurements. CC homozygotes also presented a lower incidence of a positive family history of hypertension (P = .027). No statistically significant differences among AT1 receptor A/C1166 genotypes were observed for left ventricular mass or carotid artery wall thickness. We conclude that the present study does not support a major role of the AT1 receptor gene A/C1166 polymorphism as a marker of conditions associated with increased cardiovascular risk.

An intronic polymorphic repeat sequence modulates interleukin-1 α gene regulation

Article

Sep 1996
MOL IMMUNOL

Recently, we characterized a polymorphism within IL-1 alpha intron 6 as a variable number of a 46 bp tandem repeat (ranging from 5 to 18 repeats). We now analyse whether this polymorphism could play a role in IL-1 alpha gene regulation. We have found that reporter gene expression driven by the IL-1 alpha promoter or a heterologous promoter was decreased by increasing numbers of the repeat sequence corresponding to the most frequent alleles seen in the human population. Furthermore, we showed that the transcription factor Sp1 can bind to the 46 bp sequence. Finally, we were unable to show a statistically-significant relation between in vitro IL-1 alpha production and the number of repeats although there was a clear trend towards an inverse relation. Taken together, these results are consistent with a negative regulatory role for IL-1 alpha intron 6 repeat sequence on IL-1 alpha basal gene transcription.

Four weeks of cycle training increases basal production of nitric oxide in the forearm

Article

Apr 1997
Am J Physiol

The purpose of this study was to determine whether nontrained vascular beds might contribute to the beneficial effects of exercise, including reduced blood pressure by enhanced nitric oxide production. Thirteen healthy, sedentary male volunteers performed 4 wk of normal sedentary activity and 4 wk of cycle training in a randomized order. At the end of each intervention, venous occlusion plethysmography was used to study the forearm blood flow responses to intra-arterial infusions of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA), acetylcholine, and sodium nitroprusside. Training increased the maximal work-load and maximal oxygen consumption, whereas intrabrachial blood pressure was reduced. L-NMMA caused a greater vasoconstriction after training (P = 0.004). Net nitrate and nitrite consumption by the forearm was less after training both before and after administration of L-NMMA (P = 0.04), consistent with increased nitrate and nitrite production from nitric oxide metabolism. There was no difference in the response to acetylcholine or sodium nitroprusside between the two states. Preliminary studies showed an increase in forearm blood flow and blood viscosity after cycling, suggesting that elevated shear stress in this vascular bed may contribute to endothelial adaptation and the cardiovascular protective effects of exercise training.

Pulse Pressure A Predictor of Long-term Cardiovascular Mortality in a French Male Population

Article

Dec 1997

Studies on the usefulness of blood pressure as a prognostic factor in cardiovascular disease have more often involved investigations of the levels of diastolic or systolic blood pressure. However, blood pressure may be divided into two other components: steady (mean pressure) and pulsatile (pulse pressure). In this study, the relationship of pulse pressure to cardiovascular mortality was investigated in 19 083 men 40 to 69 years old who were undergoing a routine systematic health examination and were being followed up after a mean period of 19.5 years. Subjects were divided into four groups according to age (40 to 54 and 55 to 69 years) and mean arterial pressure (<107 and > or =107 mm Hg). Each group was further divided into four subgroups according to the pulse pressure level. A wide pulse pressure (evaluated according to the quartile group or as a continuous quantitative variable) was an independent and significant predictor of all-cause, total cardiovascular, and, especially, coronary mortality in all age and mean pressure groups. No significant association between pulse pressure and cerebrovascular mortality was observed. In conclusion, in a large population of men with a relatively low cardiovascular risk, a wide pulse pressure is a significant independent predictor of all-cause, cardiovascular, and, especially, coronary mortality.

Independent prognostic information provided by sphygmomanometrically determined pulse pressure and mean arterial pressure in patients with left ventricular dysfunction

Article

Apr 1999
J AM COLL CARDIOL

The purpose of this study was to evaluate the relationship of baseline pulse pressure and mean arterial pressure to mortality in patients with left ventricular dysfunction. Increased conduit vessel stiffness increases pulse pressure and pulsatile load, potentially contributing to adverse outcomes in patients with left ventricular dysfunction. Pulse and mean arterial pressure were analyzed for their effect on mortality, adjusting for other modifiers of risk, using Cox proportional hazards regression analysis of data collected from 6,781 patients randomized into the Studies of Left Ventricular Dysfunction trials. Pulse and mean arterial pressure were related positively to each other, age, ejection fraction and prevalence of diabetes and hypertension and inversely to prior myocardial infarction and beta-adrenergic blocking agent use. Higher pulse pressure was associated with increased prevalence of female gender, greater calcium channel blocking agent, digoxin and diuretic use, lower heart rate and a higher rate of reported smoking history. Higher mean arterial pressure was associated with higher heart rate, lower calcium channel blocker and digoxin use and lower New York Heart Association functional class. Over a 61-month follow-up 1,582 deaths (1,397 cardiovascular) occurred. In a multivariate analysis adjusting for the above covariates and treatment assignment, higher pulse pressure remained an independent predictor of total and cardiovascular mortality (total mortality relative risk, 1.05 per 10 mm Hg increment; 95% confidence interval, 1.01 to 1.10; p = 0.02). Mean arterial pressure was inversely related to total and cardiovascular mortality (total mortality relative risk, 0.89; 95% confidence interval, 0.85 to 0.94; p <0.0001). One noninvasive blood pressure measurement provides two independent prognostic factors for survival. Increased conduit vessel stiffness, as assessed by pulse pressure, may contribute to increased mortality in patients with left ventricular dysfunction, independent of mean arterial pressure.

Central Pulse Pressure Is a Major Determinant of Ascending Aorta Dilation in Marfan Syndrome

Article

May 1999
CIRCULATION

In patients with Marfan syndrome (MFS), brachial pulse pressure (PP) has been recognized as a risk factor for aortic dilatation, leading to aortic dissection, the main cause of premature death. However, the relationships between aortic PP, aortic stiffness, and aortic root dilation have not been investigated. Our main objective was to determine whether central PP, which takes into account wave reflections and aortic stiffness, is a better determinant of ascending aorta diameter than brachial PP in MFS patients. Twenty patients with confirmed MFS and 20 age- and sex-matched control subjects were included in this cross-sectional, noninvasive study. Elastic properties of the abdominal aorta and common carotid, common femoral, and radial arteries were calculated from the pulsatile changes in arterial diameter and pressure. The ascending aorta diameter, measured with conventional echocardiography, was 37% larger in MFS than in control subjects (P<0.001). Arterial distensibility was 38% lower in MFS than in control subjects at the site of the abdominal aorta (P<0.01) but not at other sites (common carotid, common femoral, and radial arteries). Independently of age and body surface area, ascending aorta diameter was positively correlated with carotid PP in MFS (P<0. 01) and negatively in control subjects (P<0.01) but was not correlated with brachial PP and mean blood pressure. In patients with MFS, local PP, estimated from carotid PP, was a major determinant of ascending aorta diameter, whereas brachial PP was not. Increased arterial stiffness was confined to the aorta.

Clustering of mutations associated with mild Marfan-like phenotypes in the 3´ region of FBN1 suggests a potential genotype-phenotype correlation

Article

Apr 2000

Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome, a dominantly inherited disorder of connective tissue that primarily involves the cardiovascular, ocular, and skeletal systems. There is a remarkable degree of variability both within and between families with Marfan syndrome, and FBN1 mutations have also been found in a range of other related connective tissue disorders collectively termed type-1 fibrillinopathies. FBN1 mutations have been found in almost all of the 65 exons of the FBN1 gene and for the most part have been unique to one affected patient or family. Aside from the "hot spots" for the neonatal Marfan syndrome in exons 24-27 and 31-32, genotype-phenotype correlations have been slow to emerge. Here we present the results of temperature-gradient gel electrophoresis analysis of FBN1 exons 59-65. Six mutations were identified, only one of which had been previously reported. Two of the six mutations were found in patients with mild phenotypes. Taken together with other published reports, our results suggest that a sizable subset (ca. 40%) of mutations in this region is associated with mild phenotypes characterized by the lack of significant aortic pathology, compared with about 7% in the rest of the gene. In two cases, mutations affecting analogous positions within one of the 43 cbEGF modules of FBN1 are associated with mild phenotypes when found in one of the 6 C-terminal modules (encoded by exons 59-63), but are associated with classic or severe phenotypes when found in cbEGF modules elsewhere in the gene.

Splicing factors induce CFTR exon 9 skipping through a non-evolutionary conserved intronic element

Article

Aug 2000

In monosymptomatic forms of cystic fibrosis such as congenital bilateral absence of vas deferens, variations in the TGm and Tn polymorphic repeats at the 3′ end of intron 8 of the cystic fibrosis transmembrane regulator (CFTR) gene are associated with the alternative splicing of exon 9, which results in a nonfunctional CFTR protein. Using a minigene model system, we have previously shown a direct relationship between the TGmTn polymorphism and exon 9 splicing. We have now evaluated the role of splicing factors in the regulation of the alternative splicing of this exon. Serine-arginine-rich proteins and the heterogeneous nuclear ribonucleoprotein A1 induced exon skipping in the human gene but not in its mouse counterpart. The effect of these proteins on exon 9 exclusion was strictly dependent on the composition of the TGm and Tn polymorphic repeats. The comparative and functional analysis of the human and mouse CFTR genes showed that a region of about 150 nucleotides, present only in the human intron 9, mediates the exon 9 splicing inhibition in association with exonic regulatory elements. This region, defined as the CFTR exon 9 intronic splicing silencer, is a target for serine-arginine-rich protein interactions. Thus, the nonevolutionary conserved CFTR exon 9 alternative splicing is modulated by the TGm and Tn polymorphism at the 3′ splice region, enhancer and silencer exonic elements, and the intronic splicing silencer in the proximal 5′ intronic region. Tissue levels and individual variability of splicing factors would determine the penetrance of the TGmTn locus in monosymptomatic forms of cystic fibrosis.

Fibrillin-rich microfibrils of the extracellular matrix: Ultrastructure and assembly

Article

Mar 2001
MICRON

Fibrillin-rich microfibrils are a unique class of extensible connective tissue macromolecules. Their critical contribution to the establishment and maintenance of diverse extracellular matrices was underlined by the linkage of their principal structural component fibrillin to Marfan syndrome, a heritable connective tissue disorder with pleiotropic manifestations. Microscopy and preparative techniques have contributed substantially to the understanding of microfibril structure and function. The supramolecular organisation of microfibrillar assemblies in tissues has been examined by tissue sectioning and X-ray diffraction methods. Published findings are discussed and new information reported on the organisation of microfibrils in the ciliary zonular fibrils by environmental scanning electron microscopy. This review summarises microscopy and X-ray diffraction studies that are informing current understanding of the ultrastructure of fibrillin-rich microfibrils.

Pulse pressure - A review of mechanisms and clinical relevance

Article

Apr 2001
J AM COLL CARDIOL

The goal of this study was to review the origin, clinical relevance and treatment of pulse pressure (PP). Elevated PP is increasingly being recognized as a risk factor for cardiovascular, particularly coronary, disease. Pulse pressure is discussed in terms of both Windkessel and distributive models of the arterial circulation. Pulse pressure arises from the interaction of cardiac ejection (stroke volume) and the properties of the arterial circulation. An increased stiffness of the aorta and large arteries leads to an increase in PP through a reduction in arterial compliance and effects on wave reflection. A number of factors are known to influence arterial wall behavior and, therefore, PP. In addition to the effects of aging and blood pressure on arterial wall elasticity, there is some evidence that atherosclerosis, per se, amplifies these effects. Thus, the relationship between PP and coronary disease may be bidirectional. A number of dietary and lifestyle interventions have been shown to modify large artery behavior. These include aerobic exercise training and consumption of n-3 fatty acids. Conversely, strength training is associated with an increase in arterial stiffness and a higher PP. The effects of antihypertensive medication have been extensively studied, but many studies are difficult to interpret because of concomitant change in blood pressure, and to a lesser degree, heart rate. However a number of studies do suggest direct arterial wall effects, particularly for angiotensin-converting enzyme inhibitors. A distributed compliance model of the arterial circulation provides a framework for understanding the causes, effects and potential treatment of elevations in PP.

Aortic Stiffness Is an Independent Predictor of All-Cause and Cardiovascular Mortality in Hypertensive Patients

Article

Jun 2001
Hypertension

Although various studies reported that pulse pressure, an indirect index of arterial stiffening, was an independent risk factor for mortality, a direct relationship between arterial stiffness and all-cause and cardiovascular mortality remained to be established in patients with essential hypertension. A cohort of 1980 essential hypertensive patients who attended the outpatient hypertension clinic of Broussais Hospital between 1980 and 1996 and who had a measurement of arterial stiffness was studied. At entry, aortic stiffness was assessed from the measurement of carotid-femoral pulse-wave velocity (PWV). A logistic regression model was used to estimate the relative risk of all-cause and cardiovascular deaths. Selection of classic risk factors for adjustment of PWV was based on their influence on mortality in this cohort in univariate analysis. Mean age at entry was 50+/-13 years (mean+/-SD). During an average follow-up of 112+/-53 months, 107 fatal events occurred. Among them, 46 were of cardiovascular origin. PWV was significantly associated with all-cause and cardiovascular mortality in a univariate model of logistic regression analysis (odds ratio for 5 m/s PWV was 2.14 [95% confidence interval, 1.71 to 2.67, P<0.0001] and 2.35 [95% confidence interval, 1.76 to 3.14, P<0.0001], respectively). In multivariate models of logistic regression analysis, PWV was significantly associated with all-cause and cardiovascular mortality, independent of previous cardiovascular diseases, age, and diabetes. By contrast, pulse pressure was not significantly and independently associated to mortality. This study provides the first direct evidence that aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in patients with essential hypertension.

Carotid Pressure Is a Better Predictor of Coronary Artery Disease Severity Than Brachial Pressure

Article

Oct 2001
Hypertension

The mechanisms relating pulse pressure to cardiovascular outcome may include surrogacy for coronary disease severity. Although pulse pressure is typically measured at the brachial artery, central pulse pressure and its principal determinant, large-artery stiffness, may relate more closely to disease severity. This study aimed to determine the relationships between large-artery stiffness and carotid and brachial blood pressures and coronary artery disease severity. One hundred fourteen male patients with coronary artery disease (age 60+/-8 years, mean+/-SD) and 57 age-matched healthy male controls (age 59+/-9 years) were recruited. Patients were classified into 2 groups based on the magnitude of their maximum coronary stenosis: moderate (50% to 89%) and severe (>/=90%). Large-artery stiffness was assessed as systemic arterial compliance and carotid-femoral pulse wave velocity. Mean pressure was not different between the 3 groups. Systemic compliance and carotid pulse pressure were significantly different between all 3 groups, with compliance lowest and pressure highest in the severe group (P<0.05). Pulse wave velocity was higher in patients with severe stenosis than in those with moderate stenosis (P<0.01) and those in the control group (P<0.001). Brachial pulse pressure was higher in patients than in controls (P<0.05), but there was no difference between the 2 disease groups. In separate multivariate analyses, carotid pressures and systemic arterial compliance were determinants of coronary artery disease severity, independent of age, smoking status, body mass index, mean arterial pressure, heart rate, cholesterol levels (total, LDL, and HDL), triglycerides, and beta-antagonist and lipid-lowering therapy (P<0.001), whereas brachial pressures and pulse wave velocity were not. In conclusion, central blood pressures and systemic arterial compliance are more sensitive markers of coronary artery disease severity than brachial pressures.

Fibrillin-1 Genotype Is Associated With Aortic Stiffness and Disease Severity in Patients With Coronary Artery Disease

Abstract

No full-text available

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