Showing papers in "Hypertension in 2009"

Dissociation of Aortic Pulse Wave Velocity With Risk Factors for Cardiovascular Disease Other Than Hypertension: A Systematic Review

Abstract: Carotid-femoral pulse wave velocity (cfPWV), a measure of large artery stiffness, is an important predictor of cardiovascular events. This has been attributed to it being an integrative measure of the impact of cardiovascular risk factors on the arterial wall. Pulse wave velocity is strongly associated with age and blood pressure. However, findings with regard to its relation with other risk factors have been inconsistent. We performed a systematic review of cross-sectional published literature reporting independent associations of cfPWV in multivariable regression models. Articles were selected from a PubMed search using a prespecified search strategy. Studies were included if they did the following: (1) measured cfPWV; (2) reported on associations with cfPWV from regression models; and (3) considered age and blood pressure in the model. From 637 retrieved articles, 65 met our inclusion criteria, and 12 studies were included from reference searches. Age and blood pressure were consistently independently associated with cfPWV (91% and 90% of studies, respectively). Diabetes mellitus was associated with cfPWV in 52% studies, but the strength of the association was low. The majority of studies found no independent association between cfPWV and sex, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, smoking, or body mass index. The contribution of risk factors other than age and blood pressure to cfPWV is, thus, small or insignificant. The prognostic value of cfPWV may relate to a process of arterial ageing unrelated to classic risk factors other than hypertension.

Hypertensive Pregnancy Disorders and Subsequent Cardiovascular Morbidity and Type 2 Diabetes Mellitus in the Mother

Abstract: Minimal data exist concerning the relationship between hypertensive pregnancy disorders and various subsequent cardiovascular events and the effect of type 2 diabetes mellitus on these. In a registry-based cohort study, we identified women delivering in Denmark from 1978 to 2007 with a first singleton (n=782 287) and 2 first consecutive singleton deliveries (n=536 419). The exposures were gestational hypertension and mild and severe preeclampsia. We adjusted for preterm delivery, small for gestational age, placental abruption, and stillbirth and, in a second model, we also adjusted for the development of type 2 diabetes mellitus. The end points were subsequent hypertension, ischemic heart disease, congestive heart failure, thromboembolic event, stroke, and type 2 diabetes mellitus. The risk of subsequent hypertension was increased 5.31-fold (range: 4.90 to 5.75) after gestational hypertension, 3.61-fold (range: 3.43 to 3.80) after mild preeclampsia, and 6.07-fold (range: 5.45 to 6.77) after severe preeclampsia. The risk of subsequent type 2 diabetes mellitus was increased 3.12-fold (range: 2.63 to 3.70) after gestational hypertension and 3.68-fold (range: 3.04 to 4.46) after severe preeclampsia. Women having 2 pregnancies both complicated by preeclampsia had a 6.00-fold (range: 5.40 to 6.67) increased risk of subsequent hypertension compared with 2.70-fold (range: 2.51 to 2.90) for women having preeclampsia in their first pregnancy only and 4.34-fold (range: 3.98 to 4.74) for women having preeclampsia in their second pregnancy only. The risk of subsequent thromboembolism was 1.03-fold (range: 0.73 to 1.45), 1.53-fold (range: 1.32 to 1.77), and 1.91-fold (range: 1.35 to 2.70) increased after gestational hypertension and mild and severe preeclampsia, respectively. Thus, hypertensive pregnancy disorders are strongly associated with subsequent type 2 diabetes mellitus and hypertension, the latter independent of subsequent type 2 diabetes mellitus. The severity, parity, and recurrence of these hypertensive pregnancy disorders increase the risk of subsequent cardiovascular events.

Noninvasive Assessment of Subclinical Atherosclerosis in Children and Adolescents: Recommendations for Standard Assessment for Clinical Research: A Scientific Statement From the American Heart Association

Abstract: Deterioration in endothelial function and arterial stiffness are early events in the development of cardiovascular diseases In adults, noninvasive measures of atherosclerosis have become established as valid and reliable tools for refining cardiovascular risk to target individuals who need early intervention With limited pediatric data, the use of these techniques in children and adolescents largely has been reserved for research purposes Therefore, this scientific statement was written to (1) review the current literature on the noninvasive assessment of atherosclerosis in children and adolescents, (2) make recommendations for the standardization of these tools for research, and (3) stimulate further research with a goal of developing valid and reliable techniques with normative data for noninvasive clinical evaluation of atherosclerosis in pediatric patients Precise and reliable noninvasive tests for atherosclerosis in youth will improve our ability to estimate future risk for heart attack and stroke Currently, large longitudinal studies of cardiovascular risk factors in youth, such as the Bogalusa and Muscatine studies, lack sufficient adult subjects experiencing hard outcomes, such as heart attack and stroke, to produce meaningful risk scores like those developed from Framingham data

Effects of Dietary Sodium Reduction on Blood Pressure in Subjects With Resistant Hypertension: Results From a Randomized Trial

Abstract: Observational studies indicate a significant relation between dietary sodium and level of blood pressure. However, the role of salt sensitivity in the development of resistant hypertension is unknown. The present study examined the effects of dietary salt restriction on office and 24-hour ambulatory blood pressure in subjects with resistant hypertension. Twelve subjects with resistant hypertension entered into a randomized crossover evaluation of low (50 mmol/24 hours×7 days) and high sodium diets (250 mmol/24 hours×7 days) separated by a 2-week washout period. Brain natriuretic peptide; plasma renin activity; 24-hour urinary aldosterone, sodium, and potassium; 24-hour ambulatory blood pressure monitoring; aortic pulse wave velocity; and augmentation index were compared between dietary treatment periods. At baseline, subjects were on an average of 3.4±0.5 antihypertensive medications with a mean office BP of 145.8±10.8/83.9±11.2 mm Hg. Mean urinary sodium excretion was 46.1±26.8 versus 252.2±64.6 mmol/24 hours during low- versus high-salt intake. Low- compared to high-salt diet decreased office systolic and diastolic blood pressure by 22.7 and 9.1 mm Hg, respectively. Plasma renin activity increased whereas brain natriuretic peptide and creatinine clearance decreased during low-salt intake, indicative of intravascular volume reduction. These results indicate that excessive dietary sodium ingestion contributes importantly to resistance to antihypertensive treatment. Strategies to substantially reduce dietary salt intake should be part of the overall treatment of resistant hypertension.

Role of Pulse Pressure Amplification in Arterial Hypertension: Experts’ Opinion and Review of the Data

Abstract: Arterial hypertension is a major modifiable cardiovascular (CV) risk factor worldwide based on observational studies of brachial artery blood pressure (BP) In the latest guidelines of the European Society of Hypertension1 for the management of arterial hypertension, aortic stiffness was introduced as an index of target organ damage Three additional cardinal features of BP were also acknowledged: (1) systolic BP and pulse pressure (PP) may differ between the brachial artery and central arteries (ie, the aorta and its proximal branches), (2) the effects of antihypertensive drug treatment on brachial BP does not invariably reflect those seen on central BP, and (3) central BP is significantly related to CV events Moreover, the guidelines acknowledged that noninvasive methods exist for the assessment of central hemodynamic parameters, such as central PP, and highlighted the need for large scale interventional studies that will further confirm the prognostic importance of central BP Two years ago, coincident with the 6th International Workshop on the “Structure and Function of the Vascular System,” in Paris, a consensus document on the role of central BP in arterial hypertension was published2 It concluded that there is “mounting evidence suggesting that central BP and indices correlate more closely with intermediate markers of CV risk than brachial BP” It was also suggested that clinicians and researchers need to become familiarized with the disparity between peripheral and central BPs, ie, the phenomenon of pressure wave amplification The present document is designed to address this need The left ventricle consumes energy by ejecting blood into the arterial system, thereby creating arterial blood flow and pressure This phenomenon is easily conceived as a propagating pulse along the arterial bed In daily clinical practice the arterial pulse, at a distinct site of the arterial tree (eg, at the brachial artery), is quantified as the …

Visceral Obesity. The Link Among Inflammation, Hypertension, and Cardiovascular Disease

Abstract: The worldwide epidemic of obesity, fostered by the modern lifestyle characterized by the lack of physical activity and an energy-dense diet, has contributed to create an unprecedented condition in human history where a majority of overfed individuals will soon surpass the number of malnourished.1 Obesity-associated disorders, such as diabetes mellitus, an atherogenic dyslipidemia, and hypertension, have undoubtedly contributed to create an atherosclerosis-prone environment and thereby the development of cardiovascular disease (CVD), a leading cause of mortality in Westernized societies. A growing body of evidence indicates that obesity is a heterogeneous condition in which body fat distribution is closely associated with metabolic perturbations and, thus, with CVD risk.2 In this regard, accumulation of visceral (intra-abdominal) fat is strongly associated with insulin resistance and with a typical atherogenic dyslipidemic state.3 The adipose tissue, once considered a simple energy warehouse, is now regarded as a complex organ not only contributing to the management of energy flux within the body but also interacting with the inflammatory system and the vascular wall. Furthermore, recent studies have underlined that there are intricate interplays among adipocytes, the sympathetic nervous system (SNS), and the renin-angiotensin system (RAS), which participate in the obesity-associated dysmetabolic state. Thus, the adipose tissue is believed to play an important role in the development of both hypertension and other complications related to insulin resistance. However, it should be pointed out that different fat depots have distinct metabolic characteristics, leading to individual differences in the impact of obesity on cardiometabolic risk. Herein, we reviewed the complex links among visceral adiposity, inflammation, and hypertension, along with an attempt to address the clinical implications of these interactions. ### Small, Dense Low-Density Lipoprotein By its peculiar location, the expanded visceral fat depot has easy access to the liver via the portal circulation, where it could influence metabolism and promote insulin …

Insights Into the Mechanisms and Mediators of the Effects of Air Pollution Exposure on Blood Pressure and Vascular Function in Healthy Humans

Abstract: Fine particulate matter air pollution plus ozone impairs vascular function and raises diastolic blood pressure. We aimed to determine the mechanism and air pollutant responsible. The effects of pollution on heart rate variability, blood pressure, biomarkers, and brachial flow-mediated dilatation were determined in 2 randomized, double-blind, crossover studies. In Ann Arbor, 50 subjects were exposed to fine particles (150 μg/m 3 ) plus ozone (120 parts per billion) for 2 hours on 3 occasions with pretreatments of an endothelin antagonist (Bosentan, 250 mg), antioxidant (Vitamin C, 2 g), or placebo. In Toronto, 31 subjects were exposed to 4 different conditions (particles plus ozone, particles, ozone, and filtered air). In Toronto, diastolic blood pressure significantly increased (2.9 and 3.6 mm Hg) only during particle-containing exposures in association with particulate matter concentration and reductions in heart rate variability. Flow-mediated dilatation significantly decreased (2.0% and 2.9%) only 24 hours after particle-containing exposures in association with particulate matter concentration and increases in blood tumor necrosis factor α. In Ann Arbor, diastolic blood pressure significantly similarly increased during all of the exposures (2.5 to 4.0 mm Hg), a response not mitigated by pretreatments. Flow-mediated dilatation remained unaltered. Particulate matter, not ozone, was responsible for increasing diastolic blood pressure during air pollution inhalation, most plausibly by instigating acute autonomic imbalance. Only particles from urban Toronto additionally impaired endothelial function, likely via slower proinflammatory pathways. Our findings demonstrate credible mechanisms whereby fine particulate matter could trigger acute cardiovascular events and that aspects of exposure location may be an important determinant of the health consequences.

First-Trimester Prediction of Hypertensive Disorders in Pregnancy

Abstract: This study aimed to establish a method of screening for pregnancy hypertension by a combination of maternal variables, including mean arterial pressure, uterine artery pulsatility index, pregnancy-associated plasma protein-A, and placental growth factor in early pregnancy. The base-cohort population constituted of 7797 singleton pregnancies, including 34 case subjects who developed preeclampsia (PE) requiring delivery before 34 weeks (early PE) and 123 with late PE, 136 with gestational hypertension, and 7504 cases subjects (96.3%) who were unaffected by PE or gestational hypertension. Maternal history, uterine artery pulsatility index, mean arterial pressure, and pregnancy-associated plasma protein-A were recorded in all of the cases in the base cohort, but placental growth factor was measured only in the case-control population of 209 cases who developed hypertensive disorders and 418 controls. In each case the measured mean arterial pressure, uterine artery pulsatility index, pregnancy-associated plasma protein-A, and placental growth factor were converted to a multiple of the expected median (MoM) after correction for maternal characteristics found to affect the measurements in the unaffected group. Early PE and late PE were associated with increased mean arterial pressure (1.15 MoM and 1.08 MoM) and uterine artery pulsatility index (1.53 MoM and 1.23 MoM) and decreased pregnancy-associated plasma protein-A (0.53 MoM and 0.93 MoM) and placental growth factor (0.61 MoM and 0.83 MoM). Logistic regression analysis was used to derive algorithms for the prediction of hypertensive disorders. It was estimated that, with the algorithm for early PE, 93.1%, 35.7%, and 18.3% of early PE, late PE, and gestational hypertension, respectively, could be detected with a 5% false-positive rate and that 1 in 5 pregnancies classified as being screen positive would develop pregnancy hypertension. This method of screening is far superior to the traditional approach, which relies entirely on maternal history.

Mitochondria and Reactive Oxygen Species

Abstract: Fascination by the mitochondria, “the colonial posterity of migrant prokaryocytes, probably primitive bacteria that swam into ancestral precursors of our eukaryotic cells and stayed there,”1 stems from the above-mentioned nebulous endosymbiotic theory of their origin, as well as from the growing realization of a very special role that they play in the pathogenesis of diverse diseases. These organelles generate energy primarily in the form of the electrochemical proton gradient (ΔμH+), which fuels ATP production, ion transport, and metabolism.2 Generation of this universal energy currency, ΔμH+, occurs through the series of oxidative reactions conducted by the respiratory chain complexes at the ion-impermeable, almost cholesterol-free inner membrane. Reduced nicotinamide adenine dinucleotide represents the entry point to the complex I (reduced nicotinamide adenine dinucleotide:ubiquinone reductase), whereas the reduced ubiquinol enters the respiratory chain in the complex III (ubiquinol:cytochrome c [cyt-c] reductase) to reduce cyt-c, the electron carrier to the complex IV, cyt-c oxidase. Each of these steps generates ΔμH+ by electrogenic pumping of protons from the mitochondrial matrix to the intermembrane space and is coupled to electron flow, thus generating the electric membrane potential of −180 to −220 mV and a pH gradient of 0.4 to 0.6 U across the inner mitochondrial membrane resulting in the negatively charged matrix side of the membrane and alkaline matrix. Ultimately, accumulated ΔμH+ is converted into the influx of protons into the matrix driving ATP synthesis or protein transport. In addition, these end points are necessary for the execution of 2 major enzymatic metabolic pathways within the mitochondrial matrix: the tricarboxylic acid (TCA) oxidation cycle and the fatty acid β-oxidation pathway. This intricate system fueling cellular functions is as elegant as it is vulnerable: practically every component of the system, from the electron transport chain complexes to the permeability properties of the membranes, is a …

Assessment of Sympathetic Cardiovascular Drive in Human Hypertension Achievements and Perspectives

Abstract: Methodological refinements in the assessment of human sympathetic cardiovascular drive have allowed throughout the years to better define the role of the sympathetic nervous system in the pathophysiology of hypertension. Earlier studies have provided evidence that indirect markers of adrenergic drive, such as plasma or urinary norepinephrine as well as heart rate, often display an increase in the hypertensive state. Direct recording of efferent postganglionic muscle sympathetic nerve traffic via microneurography and regional norepinephrine spillover technique have conclusively documented the occurrence of an adrenergic overdrive in hypertension, showing that the sympathetic activation is directly related to the severity of the hypertensive state and is widespread to different cardiovascular districts. The present review will focus on some major features of the "neuroadrenergic hypothesis of hypertension." In particular it will examine the mechanisms responsible for the adrenergic overdrive, the relationships between the sympathetic activation and the metabolic disarray of frequent detection in the hypertensive state, and the participation of neuroadrenergic factors at the development of the hypertension-related target organ damage. Further issues addressed will be the contribution of the hyperadrenergic state to the different patterns of the 24-hour blood pressure profile as well as to the day/night blood pressure variability described in the hypertensive state and the behavior of the sympathetic function in the hypertensive states complicated by the presence of other cardiovascular or metabolic disease. Finally, the clinical and therapeutic implications of the neuroadrenergic abnormalities occurring in hypertension, as well as the areas worthy of future research, will be highlighted.

Renal Denervation as a Therapeutic Approach for Hypertension: Novel Implications for an Old Concept

Abstract: Hypertension, heart failure, and chronic kidney disease represent a significant and growing global health issue. Current therapeutic strategies for these conditions are mainly based on lifestyle interventions and pharmacological approaches, but the rates of control of blood pressure and the therapeutic efforts to prevent progression of heart failure, chronic kidney disease, and their sequelae remain unsatisfactory, and additional options are required. The contribution of renal sympathetic nerve activity to the development and progression of these disease states has been convincingly demonstrated in both preclinical and human experiments. Preclinical experiments in models of hypertension, myocardial infarction, heart failure, chronic kidney disease, and diabetic nephropathy have successfully used renal denervation as both an experimental tool and a therapeutic strategy.1–6 In the absence of appropriate drugs to pharmacologically reduce blood pressure in severely hypertensive patients, therapeutic splanchnicectomy and even radical surgical sympathectomy were used since the 1930s. In patients with end stage renal disease (ESRD) and uncontrollable hypertension, an even more radical approach, such as bilateral nephrectomy, is sometimes considered. Surgical renal denervation has been shown to be an effective means of reducing sympathetic outflow to the kidneys, increasing urine output (natriuresis and diuresis), and reducing renin release, without adversely affecting other functions of the kidney, such as glomerular filtration rate and renal blood flow. The human transplant experience has clearly demonstrated that the denervated kidney reliably supports electrolyte and volume homeostasis in free-living humans. On the basis of these findings and in view of the demand for alternative treatment options, targeting the renal sympathetic nerves as a major player in the pathophysiology of hypertension, kidney disease, and heart failure is a very attractive therapeutic approach. ### Role of Renal Sympathetic Nerves in Cardiovascular and Kidney Disease The renal sympathetic nervous system has been identified as a major contributor to the complex pathophysiology of hypertension, states of volume overload (such as heart failure), …

Dry-Weight Reduction in Hypertensive Hemodialysis Patients (DRIP) A Randomized, Controlled Trial

Abstract: Volume excess is thought to be important in the pathogenesis of hypertension among hemodialysis patients. To determine whether additional volume reduction will result in improvement in blood pressure (BP) among hypertensive patients on hemodialysis and to evaluate the time course of this response, we randomly assigned long-term hypertensive hemodialysis patients to ultrafiltration or control groups. The additional ultrafiltration group (n=100) had the dry weight probed without increasing time or duration of dialysis, whereas the control group (n=50) only had physician visits. The primary outcome was change in systolic interdialytic ambulatory BP. Postdialysis weight was reduced by 0.9 kg at 4 weeks and resulted in -6.9 mm Hg (95% CI: -12.4 to -1.3 mm Hg; P=0.016) change in systolic BP and -3.1 mm Hg (95% CI: -6.2 to -0.02 mm Hg; P=0.048) change in diastolic BP. At 8 weeks, dry weight was reduced 1 kg, systolic BP changed -6.6 mm Hg (95% CI: -12.2 to -1.0 mm Hg; P=0.021), and diastolic BP changed -3.3 mm Hg (95% CI: -6.4 to -0.2 mm Hg; P=0.037) from baseline. The Mantel-Hanzel combined odds ratio for systolic BP reduction of > or =10 mm Hg was 2.24 (95% CI: 1.32 to 3.81; P=0.003). There was no deterioration seen in any domain of the kidney disease quality of life health survey despite an increase in intradialytic signs and symptoms of hypotension. The reduction of dry weight is a simple, efficacious, and well-tolerated maneuver to improve BP control in hypertensive hemodialysis patients. Long-term control of BP will depend on continued assessment and maintenance of dry weight.

Prevalence and Factors Associated With Circadian Blood Pressure Patterns in Hypertensive Patients

Abstract: Ambulatory blood pressure (BP) monitoring has become useful in the diagnosis and management of hypertensive individuals. In addition to 24-hour values, the circadian variation of BP adds prognostic significance in predicting cardiovascular outcome. However, the magnitude of circadian BP patterns in large studies has hardly been noticed. Our aims were to determine the prevalence of circadian BP patterns and to assess clinical conditions associated with the nondipping status in groups of both treated and untreated hypertensive subjects, studied separately. Clinical data and 24-hour ambulatory BP monitoring were obtained from 42,947 hypertensive patients included in the Spanish Society of Hypertension Ambulatory Blood Pressure Monitoring Registry. They were 8384 previously untreated and 34,563 treated hypertensives. Twenty-four-hour ambulatory BP monitoring was performed with an oscillometric device (SpaceLabs 90207). A nondipping pattern was defined when nocturnal systolic BP dip was <10% of daytime systolic BP. The prevalence of nondipping was 41% in the untreated group and 53% in treated patients. In both groups, advanced age, obesity, diabetes mellitus, and overt cardiovascular or renal disease were associated with a blunted nocturnal BP decline (P<0.001). In treated patients, nondipping was associated with the use of a higher number of antihypertensive drugs but not with the time of the day at which antihypertensive drugs were administered. In conclusion, a blunted nocturnal BP dip (the nondipping pattern) is common in hypertensive patients. A clinical pattern of high cardiovascular risk is associated with nondipping, suggesting that the blunted nocturnal BP dip may be merely a marker of high cardiovascular risk.

Mitochondria-Targeted Antioxidant MitoQ10 Improves Endothelial Function and Attenuates Cardiac Hypertrophy

Abstract: Mitochondria are a major site of reactive oxygen species production, which may contribute to the development of cardiovascular disease. Protecting mitochondria from oxidative damage should be an effective therapeutic strategy; however, conventional antioxidants are ineffective, because they cannot penetrate the mitochondria. This study investigated the role of mitochondrial oxidative stress during development of hypertension in the stroke-prone spontaneously hypertensive rat, using the mitochondria-targeted antioxidant, MitoQ(10). Eight-week-old male stroke-prone spontaneously hypertensive rats were treated with MitoQ(10) (500 mumol/L; n=16), control compound decyltriphenylphosphonium (decylTPP; 500 mumol/L; n=8), or vehicle (n=9) in drinking water for 8 weeks. Systolic blood pressure was significantly reduced by approximately 25 mm Hg over the 8-week MitoQ(10) treatment period compared with decylTPP (F=5.94; P=0.029) or untreated controls (F=65.6; P=0.0001). MitoQ(10) treatment significantly improved thoracic aorta NO bioavailability (1.16+/-0.03 g/g; P=0.002, area under the curve) compared with both untreated controls (0.68+/-0.02 g/g) and decylTPP-treated rats (0.60+/-0.06 g/g). Cardiac hypertrophy was significantly reduced by MitoQ(10) treatment compared with untreated control and decylTPP treatment (MitoQ(10): 4.01+/-0.05 mg/g; control: 4.42+/-0.11 mg/g; and decylTPP: 4.40+/-0.09 mg/g; ANOVA P=0.002). Total MitoQ(10) content was measured in liver, heart, carotid artery, and kidney harvested from MitoQ(10)-treated rats by liquid chromatography-tandem mass spectrometry. All of the organs analyzed demonstrated detectable levels of MitoQ(10), with comparable accumulation in vascular and cardiac tissues. Administration of the mitochondria-targeted antioxidant MitoQ(10) protects against the development of hypertension, improves endothelial function, and reduces cardiac hypertrophy in young stroke-prone spontaneously hypertensive rats. MitoQ(10) provides a novel approach to attenuate mitochondrial-specific oxidative damage with the potential to become a new therapeutic intervention in human cardiovascular disease.

Vascular Aging A Tale of EVA and ADAM in Cardiovascular Risk Assessment and Prevention

Abstract: Cardiovascular disease (CVD) manifestations still pose a substantial threat to public health, as summarized in a recent report from the American Heart Association Statistics Committee for an update in 2009.1 Classic risk factors are of major importance to screen for, to evaluate, and to control with lifestyle advice or drug therapy. However, because the risk of CVD is still representing a challenge in spite of prevention and all treatment efforts, there is a need for new pathophysiological models for better understanding of cardiovascular risk and its treatment, based on new concepts. It has been shown that target organ damage (TOD) represents a mediating step between risk factors and CVD events. Examples of well-established TOD categories include left ventricular hypertrophy and albumin excretion. In addition, substantial evidence has accumulated to show that arterial stiffness and increased pulse wave velocity (PWV), as well as central aortic pulse pressure, are important independent predictors of CVD events.2 These are in fact not only examples of TOD but also of the underlying pathological process, because increased PWV might determine the degree of left ventricular hypertrophy through increased arterial pulse wave reflection, central pulse pressure, and postload.2 Because aging is a common denominator to many chronic disease manifestations, eg, CVD, type 2 diabetes mellitus, or cancer, we propose that early vascular aging (EVA) could be a useful concept to better guide clinical investigations in subjects at increased cardiovascular (CV) risk. This could be the case in individuals with marginal elevation of classic risk factors or with a strong family history of early CVD manifestations. There might also be a special link between adverse growth patterns in fetal or early postnatal life (the “mismatch” growth hypothesis) and the EVA syndrome, as summarized recently.3 Vascular aging in general, and EVA more specifically, can be …

Validation of a Case Definition to Define Hypertension Using Administrative Data

Abstract: We validated the accuracy of case definitions for hypertension derived from administrative data across time periods (year 2001 versus 2004) and geographic regions using physician charts. Physician charts were randomly selected in rural and urban areas from Alberta and British Columbia, Canada, during years 2001 and 2004. Physician charts were linked with administrative data through unique personal health number. We reviewed charts of approximately 50 randomly selected patients >35 years of age from each clinic within 48 urban and 16 rural family physician clinics to identify physician diagnoses of hypertension during the years 2001 and 2004. The validity indices were estimated for diagnosed hypertension using 3 years of administrative data for the 8 case-definition combinations. Of the 3,362 patient charts reviewed, the prevalence of hypertension ranged from 18.8% to 33.3%, depending on the year and region studied. The administrative data hypertension definition of "2 claims within 2 years or 1 hospitalization" had the highest validity relative to the other definitions evaluated (sensitivity 75%, specificity 94%, positive predictive value 81%, negative predictive value 92%, and kappa 0.71). After adjustment for age, sex, and comorbid conditions, the sensitivities between regions, years, and provinces were not significantly different, but the positive predictive value varied slightly across geographic regions. These results provide evidence that administrative data can be used as a relatively valid source of data to define cases of hypertension for surveillance and research purposes.

[Pyr1]Apelin-13 Identified as the Predominant Apelin Isoform in the Human Heart. Vasoactive Mechanisms and Inotropic Action in Disease

Abstract: Apelin receptors, present on vascular smooth muscle cells, endothelium, and cardiomyocytes, are activated by the family of apelin peptides to elicit cardiovascular effects in experimental animals, but functional activity in humans has not been studied in detail. We detected low levels of apelin immunoreactivity in plasma of volunteers consistent with an autocrine/paracrine action and detected apelin immunoreactivity in the supernatant from human cultured endothelial cells. We found that [Pyr(1)]apelin-13 was the predominant isoform in cardiac tissue from patients with coronary artery disease. We tested the hypothesis that apelins have vascular and cardiac actions in human tissues in vitro and compared responses to [Pyr(1)]apelin-13, apelin-13, and apelin-36. In endothelium-intact mammary artery, all 3 of the apelins induced concentration-dependent vasodilatation with comparable potency (EC(50): 0.6 to 1.6 nM; maximum response: 40% to 50%). Vasodilatation was abolished after endothelial removal or preincubation with indomethacin but was unaffected by preincubation with N(G)-nitro-L-arginine methyl ester, indicating involvement of prostanoids but not NO in dilatation by apelins in this patient group. Apelins were potent constrictors of endothelium-denuded saphenous vein (EC(50): 0.6 to 1.6 nM; maximum response: 17% to 26%) and mammary artery ([Pyr(1)]apelin-13; EC(50): 0.2 nM; maximum response: 29%). In paced atrial strips, all 3 of the peptides increased the force of contraction with subnanomolar potencies (EC(50): 40 to 125 pM). For the first time, we demonstrate that the 3 principal forms of apelin have comparable potency and efficacy in human cardiovascular tissues. Apelins are potent endothelium-dependent vasodilators acting via a prostanoid-dependent mechanism; however, removal of the endothelium revealed direct vasoconstrictor actions in both the artery and vein. Furthermore, in human cardiac tissue, the apelin peptides are among the most potent endogenous positive inotropic agents yet reported.

Impact of shear rate modulation on vascular function in humans

Abstract: Shear stress is an important stimulus to arterial adaptation in response to exercise and training in humans. We recently observed significant reverse arterial flow and shear during exercise and different antegrade/retrograde patterns of shear and flow in response to different types of exercise. The purpose of this study was to simultaneously examine flow-mediated dilation, a largely NO-mediated vasodilator response, in both brachial arteries of healthy young men before and after 30-minute interventions consisting of bilateral forearm heating, recumbent leg cycling, and bilateral handgrip exercise. During each intervention, a cuff inflated to 60 mm Hg was placed on 1 arm to unilaterally manipulate the shear rate stimulus. In the noncuffed arm, antegrade flow and shear increased similarly in response to each intervention (ANOVA; P<0.001, no interaction between interventions; P=0.71). Baseline flow-mediated dilation (4.6%, 6.9%, and 6.7%) increased similarly in response to heating, handgrip, and cycling (8.1%, 10.4%, and 8.9%, ANOVA; P<0.001, no interaction; P=0.89). In contrast, cuffed arm antegrade shear rate was lower than in the noncuffed arm for all of the conditions (P<0.05), and the increase in flow-mediated dilation was abolished in this arm (4.7%, 6.7%, and 6.1%; 2-way ANOVA: all conditions interacted P<0.05). These results suggest that differences in the magnitude of antegrade shear rate transduce differences in endothelial vasodilator function in humans, a finding that may have relevance for the impact of different exercise interventions on vascular adaptation in humans.

Retrograde flow and shear rate acutely impair endothelial function in humans.

Abstract: Changes in arterial shear stress induce functional and structural vasculature adaptations. Recent studies indicate that substantial retrograde flow and shear can occur through human conduit arteries. In animals, retrograde shear is associated with atherogenic effects. The aim of this study was to examine the impact of incremental levels of retrograde shear on endothelial function in vivo. On 3 separate days, we examined bilateral brachial artery flow-mediated dilation, an index of NO-mediated endothelial function, in healthy men (243 years) before and after a 30-minute intervention consisting of cuff inflation to 25, 50, or 75 mm Hg. Cuff inflations resulted in "dose"-dependent increases in retrograde shear rate, compared with the noncuffed arm, within subjects (P0.001). Flow-mediated dilation in the cuffed arm did not change in response to the 25-mm Hg stimulus but decreased significantly after both the 50- and 75-mm Hg interventions (P0.05). The decrease in flow-mediated dilation after the 75-mm Hg intervention was significantly larger than that observed after a 50-mm Hg intervention (P0.03). In the noncuffed arm, no changes in shear rate or flow-mediated dilation were observed. These results demonstrate that an increase in retrograde shear rate induces a dose-dependent attenuation of endothelial function in humans. This finding contributes to our understanding regarding the possible detrimental effects of retrograde shear rate in vivo. (Hypertension. 2009;53:986-992.)

Sex Differences in Sympathetic Neural-Hemodynamic Balance Implications for Human Blood Pressure Regulation

Abstract: Among young normotensive men, a reciprocal balance between cardiac output and sympathetic nerve activity is important in the regulation of arterial pressure. In young women, the balance among cardiac output, peripheral resistance, and sympathetic nerve activity is unknown. Consequently, the aim of this study was to examine the relationship of cardiac output and total peripheral resistance to muscle sympathetic nerve activity in young women. Multiunit peroneal recordings of muscle sympathetic nerve activity were obtained in 17 women (mean+/-SEM: age 24+/-3 years) and 21 men (mean+/-SEM: age 25+/-5 years). Mean resting muscle sympathetic nerve activity was lower in women compared with men (19+/-3 versus 25+/-1 bursts minute(-1); P 0.05) or cardiac output (r=0.23; P>0.05) in women. Our results demonstrate that men and women rely on different integrated physiological mechanisms to maintain a normal arterial pressure despite widely varying sympathetic nerve activity among individuals. These findings may have important implications for understanding how hypertension and other disorders of blood pressure regulation occur in men and women.

Regression of Left Ventricular Mass by Antihypertensive Treatment A Meta-Analysis of Randomized Comparative Studies

Abstract: Blood pressure–lowering therapy reduces left ventricular mass, but the question of whether differences exist among drug classes has not been fully resolved. Our aim was to compare the effects of diuretics, β-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers on left ventricular mass regression in patients with hypertension on the basis of prospective, randomized comparative studies. We performed meta-analyses, involving pooled pairwise comparisons of the drug classes and of each class versus other classes statistically combined, and meta-regression analyses to identify the determinants of the regression. The 75 relevant publications involved 84 pairwise comparisons and 6001 patients. Regression of left ventricular mass was significantly less ( P =0.01) with β-blockers (9.8%) than with angiotensin receptor blockers (12.5%), but none of the other analyzable pairwise comparisons between drug classes revealed significant differences ( P >0.10). In addition, β-blockers showed less regression than the other 4 classes statistically combined ( P P P

Long-Term Risk of Sustained Hypertension in White-Coat or Masked Hypertension

Abstract: It is debated whether white-coat (WCHT) and masked hypertension (MHT) are at greater risk of developing a sustained hypertensive state (SHT). In 1412 subjects of the Pressioni Arteriose Monitorate e Loro Associazioni Study, we measured office blood pressure (BP), 24-hour ambulatory BP, and home BP. The condition of WCHT was identified as office BP >140/90 mm Hg and 24-hour BP mean or =125/79 mm Hg, and home BP >or =132/82 mm Hg. SHT was identified when both office and 24-hour BP means or home BP were over threshold values and normotension was under the threshold value. Subjects were reassessed 10 years later to evaluate the BP status of the various conditions defined previously. At the first examination, 758 (54.1%), 225 (16.1%), 124 (8.9%), and 293 (20.9%) subjects were normotensive, WCHT, MHT, and SHT subjects, respectively. At the second examination, 136 normotensives (18.2%), 95 WCHT (42.6%), and 56 MHT (47.1%) subjects became SHT. As compared with normotensives, adjusting for age and sex, the risk of becoming SHT was significantly higher for WCHT and MHT subjects (odds ratio: 2.51 and 1.78, respectively; P<0.0001). Similar results were obtained when the definition of the various conditions was based on home BP. Independent contributors of worsening of hypertension status were not only baseline BP, but also, although to a lesser extent, metabolic variables and age. Subjects with WCHT and MHT are at increased risk of developing SHT. This may contribute to their prognosis that appears to be worse as compared with that of normotensive subjects.

Depression is associated with decreased blood pressure, but antidepressant use increases the risk for hypertension

Abstract: The present study compared blood pressure levels between subjects with clinical anxiety and depressive disorders with healthy controls. Cross-sectional data were obtained in a large cohort study, t...

Deletion of Mineralocorticoid Receptors From Macrophages Protects Against Deoxycorticosterone/Salt-Induced Cardiac Fibrosis and Increased Blood Pressure

Abstract: Increased mineralocorticoid levels plus high salt promote vascular inflammation and cardiac tissue remodeling. Mineralocorticoid receptors are expressed in many cell types of the cardiovascular system, including monocytes/macrophages and other inflammatory cell types. Although mineralocorticoid receptors are expressed in monocytes/macrophages, their role in regulating macrophage function to date has not been investigated. We, thus, used the Cre/LoxP-recombination system to selectively delete mineralocorticoid receptors from monocytes/macrophages with the lysozyme M promoter used to drive Cre expression (MR(flox/flox)/LysM(Cre/-) mice). Male mice from each genotype (MR(flox/flox) or wild-type and MR(flox/flox)/LysM(Cre/-) mice) were uninephrectomized, given 0.9% NaCl solution to drink, and treated for 8 days or 8 weeks with either vehicle (n=10) or deoxycorticosterone (n=10). Equivalent tissue macrophage numbers were seen for deoxycorticosterone treatment of each genotype at 8 days; in contrast, plasminogen activator inhibitor type 1 and NAD(P)H oxidase subunit 2 levels were increased in wild-type but not in MR(flox/flox)/LysM(Cre/-) mice given deoxycorticosterone. Baseline expression of other inflammatory genes was reduced in MR(flox/flox)/LysM(Cre/-) mice compared with wild-type mice. At 8 weeks, deoxycorticosterone-induced macrophage recruitment and connective tissue growth factor and plasminogen activator inhibitor type 1 mRNA levels were similar for each genotype; in contrast, MR(flox/flox)/LysM(Cre/-) mice showed no increase in cardiac fibrosis or blood pressure, as was seen in wild-type mice at 8 weeks. These data demonstrate the following points: (1) mineralocorticoid receptor signaling regulates basal monocyte/macrophage function; (2) macrophage recruitment is not altered by loss of mineralocorticoid receptor signaling in these cells; and (3) a novel and significant role is seen for macrophage signaling in the regulation of cardiac remodeling and systolic blood pressure in the deoxycorticosterone/salt model.

Continued Improvement in Hypertension Management in England. Results From the Health Survey for England 2006

Abstract: This study evaluate whether blood pressure management has improved in England between 2003 and 2006, using cross-sectional, nationally representative, random samples of 8834 (in 2003) and 7478 (in 2006) noninstitutionalized adults (aged > or =16 years) of mean age 46 (in 2003) and 47 (in 2006) years. Overall mean blood pressure levels in 2006 were 130.8/74.2 mm Hg in men and 124.0/72.4 mm Hg in women. Awareness of hypertension increased significantly in the overall population (from 62% in 2003% to 66% in 2006; P or =2 drugs were used, the most common antihypertensive class used varied by age and ethnicity. Awareness, treatment, and control of hypertension increased between 2003 and 2006, particularly in women, but opportunities for further improvement remain.

Disparate Estimates of Hypertension Control From Ambulatory and Clinic Blood Pressure Measurements in Hypertensive Kidney Disease

Abstract: Ambulatory blood pressure (ABP) monitoring provides unique information about day-night patterns of blood pressure (BP). The objectives of this article were to describe ABP patterns in African Ameri...

Soluble Form of the (Pro)Renin Receptor Generated by Intracellular Cleavage by Furin Is Secreted in Plasma

Abstract: The (pro)renin receptor [(P)RR] is a 35-kDa transmembrane protein that plays a pivotal role in angiotensin tissue generation and in nonproteolytic prorenin activation. We detected a soluble form of (P)RR [s(P)RR; 28 kDa] in the conditioned medium of cultured cells. The aims of our study were to identify the protease responsible for the generation of s(P)RR, the site of shedding, and to establish the existence of circulating s(P)RR in plasma. We identified furin as the protease responsible for the shedding of endogenous (P)RR based on the following: LoVo colon carcinoma cells devoid of active furin synthesize full-length (P)RR but do not secrete s(P)RR; transfection of Chinese hamster ovary cells with a plasmid coding for α1-antitrypsin Portland variant, an inhibitor of furin, completely inhibited the generation of s(P)RR, whereas addition of GM6001, an inhibitor of metalloproteases or of tumor necrosis factor-α protease inhibitor-1, an inhibitor of ADAM17, in the culture medium has no effect; when the cDNA coding for (P)RR was translated in vitro and incubated with recombinant furin or ADAM17, only furin was able to generate the 28 kDa-s(P)RR, and mutagenesis in the potential furin cleavage R275A/KT/R278A site abolished s(P)RR generation. Immunofluorescence study in glomerular epithelial cells showed that (P)RR was cleaved in the trans-Golgi, and coprecipitation experiments with renin showed that s(P)RR was present in plasma. In conclusion, our results show that s(P)RR is generated intracellularly by furin cleavage, and that s(P)RR detected in plasma is able to bind renin.

Vascular Endothelial Growth Factor Receptor 2 Controls Blood Pressure by Regulating Nitric Oxide Synthase Expression

Abstract: Drugs and antibodies that interrupt vascular endothelial growth factor (VEGF) signaling pathways improve outcomes in patients with a variety of cancers by inhibiting tumor angiogenesis. A major adverse effect of these treatments is hypertension, suggesting a critical role for VEGF in blood pressure (BP) regulation. However, the physiological mechanisms underlying the control of BP by VEGF are unclear. To address this question, we administered a specific antibody against the major VEGF receptor, VEGFR2, to normal mice and assessed the consequences on BP. Compared with vehicle-treated controls, administration of the anti-VEGFR2 antibody caused a rapid and sustained increase in BP of ≈10 mm Hg. This increase in BP was associated with a significant reduction in renin mRNA expression in the kidney ( P =0.019) and in urinary excretion of aldosterone ( P N ω -nitro-l-arginine methyl ester (l-NAME) (20 mg/kg per day), an inhibitor of NO production. l-NAME administration abolished the difference in BP between the vehicle- and anti-VEGFR2–treated groups. Our data suggest that VEGF, acting via VEGFR2, plays a critical role in BP control by promoting NO synthase expression and NO activity. Interfering with this pathway is likely to be one mechanism underlying hypertension caused by antiangiogenic agents targeting VEGF.

Angiotensin II Induces Connective Tissue Growth Factor and Collagen I Expression via Transforming Growth Factor–β–Dependent and –Independent Smad Pathways. The Role of Smad3

Abstract: Connective tissue growth factor (CTGF) plays a critical role in angiotensin II (Ang II)–mediated hypertensive nephropathy. The present study investigated the mechanisms and specific roles of individual Smads in Ang II–induced CTGF and collagen I expression in tubular epithelial cells with deletion of transforming growth factor (TGF)-β1, overexpression of Smad7, or knockdown of Smad2 or Smad3. We found that Ang II–induced tubular CTGF and collagen I mRNA and protein expressions were regulated positively by phosphorylated Smad2/3 but negatively by Smad7 because overexpression of Smad7-abolished Ang II–induced Smad2/3 phosphorylation and upregulation of CTGF and collagen I in vitro and in a rat model of remnant kidney disease. Additional studies revealed that, in addition to a late (24-hour) TGF-β–dependent Smad2/3 activation, Ang II also induced a rapid activation of Smad2/3 at 15 minutes and expression of CTGF and collagen I in tubular epithelial cells lacking the TGF-β gene, which was blocked by the addition of an Ang II type 1 receptor antagonist (losartan) and inhibitors to extracellular signal–regulated kinase 1/2 (PD98059) and p38 (SB203580) but not by inhibitors to Ang II type 2 receptor (PD123319) or c-Jun N-terminal kinase (SP600125), demonstrating a TGF-β–independent, Ang II type 1 receptor–mediated extracellular signal–regulated kinase/p38 mitogen-activated protein kinase cross-talk pathway in Ang II–mediated CTGF and collagen I expression. Importantly, the ability of knockdown of Smad3, but not Smad2, to inhibit Ang II–induced CTGF and collagen I expression further revealed an essential role for Smad3 in Ang II–mediated renal fibrosis. In conclusion, Ang II induces tubular CTGF expression and renal fibrosis via the TGF-β–dependent and –independent Smad3 signaling pathways, suggesting that targeting Smad3 may have therapeutic potential for hypertensive nephropathy.

Effect of Modest Salt Reduction on Blood Pressure, Urinary Albumin, and Pulse Wave Velocity in White, Black, and Asian Mild Hypertensives

Abstract: A reduction in salt intake lowers blood pressure. However, most previous trials were in whites with few in blacks and Asians. Salt reduction may also reduce other cardiovascular risk factors (eg, u...