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In JoVE (1)

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Articles by Bonita Falkner in JoVE

 JoVE Clinical and Translational Medicine

Non-invasive Assessment of Microvascular and Endothelial Function

1Department of Family and Community Medicine, Thomas Jefferson University, 2Department of Pharmacology and Experimental Therapeutics, Biostatistics Division, Thomas Jefferson University, 3Department of Internal Medicine, Thomas Jefferson University


JoVE 50008

Capillaroscopy is a non-invasive, relatively inexpensive methodology for directly visualizing the microcirculation. The forearm blood flow technique provides accepted non-invasive measures of endothelial function.

Other articles by Bonita Falkner on PubMed

Evaluation of Hypertension in Older Children and Adolescents

Hypertension occurs in children as well as adults. Unlike adults, the rates of hypertension in childhood are lower and the methods of diagnosis and evaluation vary somewhat. In the following review on the diagnosis and management of hypertension in older children, three typical cases will be discussed. Key issues in the methods and criteria used in the diagnosis of hypertension will be described. The secondary causes of hypertension in the young, the characteristics of essential hypertension, and the management of hypertension in the young will also be discussed in the context of typical cases. (c)1999 by Le Jacq Communications, Inc.

The Association Between Hypertension and Other Cardiovascular Risk Factors in Young Adult African Americans

Hypertension is a major cause of cardiovascular disease in African Americans. The excess morbidity and mortality due to cardiovascular disease in African Americans compared to Caucasians is not well explained. The purpose of this study was to examine the association between hypertension and other cardiovascular risk factors in young adult African Americans. A risk factor scoring system was developed, based on national guidelines for obesity, smoking, cholesterol levels, glucose tolerance, and blood pressure. Data from a previously studied cohort of 206 women and 117 men were analyzed for the association of hypertension with other risk factors. Among women, risk factor intensification is due to impaired glucose tolerance and obesity. Among men, intensification appears to be related to all major risk factor categories. These findings indicate that among hypertensive African Americans there is an amplification of other risk factors. The data also support the clinical management of multiple risk factors as well as the achievement of blood pressure control.

Birth Weight As a Predictor of Future Hypertension

According to the concept of "fetal programming," intrauterine conditions that impair fetal growth can program the fetus to express hypertension, as well as other chronic diseases, in later life. A model for the development of hypertension that includes the effect of the intrauterine environment on fetal growth as a mechanistic pathway contributes a new dimension in causality and is of great interest. Experimental studies that apply maneuvers to impose fetal undernutrition in animal models have developed data that support this concept. The evidence developed from epidemiologic investigations on humans is less conclusive. Overall, there tends to be a small but consistent relationship of lower birth weight with higher blood pressure (BP). For each kilogram increase in birth weight, the systolic BP is 1 to 2 mm Hg lower.

Glucose Tolerance and Cardiovascular Risk in Young Adult African Americans

Patients with type 2 diabetes have higher rates of cardiovascular events. Among African Americans, there is a higher prevalence of both cardiovascular disease and type 2 diabetes. Few studies have examined longitudinally the change in glucose tolerance in younger adult African Americans.

Are We Losing the Game? Cardiovascular Health in Minority Children

Dysmetabolic Syndrome: Multiple Risk Factors for Premature Adult Disease in an Adolescent Girl

The clinical diagnosis of dysmetabolic syndrome in an adult defines a patient with abnormal glucose metabolism (or diabetes), hypertension, hyperlipidemia, and obesity. This disorder accelerates atherosclerosis and significantly raises the risk for cardiovascular events. With the marked rise in the prevalence of obesity in childhood, obesity-linked risk factors are being expressed at young ages. The case of a 12-year-old girl with dysmetabolic syndrome is described and discussed. Emerging clinical data now indicate that the presence of 1 risk factor for cardiovascular disease in an overweight child should prompt screening for additional clinical abnormalities, with the aim of finding treatable disorders.

Obesity, Smoking, and Multiple Cardiovascular Risk Factors in Young Adult African Americans

To examine the associations between the combination of obesity and tobacco use and total cardiovascular risk score in young adult African Americans.

Insulin Resistance in African Americans

Hypertension and diabetes mellitus are the leading contributors to end-stage renal disease. African Americans suffer higher rates of renal failure as well as other vascular morbidities associated with hypertension and diabetes. Insulin resistance is strongly associated with hypertension. Insulin resistance is a component of diabetes and also precedes the clinical expression of type 2 diabetes. The relationship of blood pressure with insulin resistance, or impaired insulin action, occurs in African Americans and can be detected at young ages prior to the clinical expression of hypertension or diabetes. Through its relationship with hypertension, diabetes, and hyperlipidemia, insulin resistance is associated with endothelial dysfunction. The interface of insulin resistance with endothelial dysfunction may begin to explain the role of insulin resistance in vascular and renal pathology. The injury process, subsequent to both hypertension and diabetes, appears to be mediated by alterations tissue regulatory factors, and include vasoactive peptides such as angiotensin II, endothelin, and growth factors. Understanding the determinants that up-regulate the aberrant pathways and the early phases of these processes will be necessary to formulate strategies to effectively achieve renal protection and reduce the rates of renal failure in African Americans.

Successful 2 Years of Therapy

Plasma Homocysteine Concentration and Blood Pressure in Young Adult African Americans

An association of plasma homocysteine concentration ([Hcy]) with cardiovascular events has been described, but the role of [Hcy] in the early phase of cardiovascular disease is uncertain. The purpose of this study was to determine whether [Hcy] is related to blood pressure (BP) or other risk factors in African Americans, a population at high risk for cardiovascular disease.

Obesity: Clinical Impact and Interventions That Work: an Update

Effect of Birth Weight on Blood Pressure and Body Size in Early Adolescence

The fetal programming theory that birth weight contributes to blood pressure or body size in later life is examined in this study. A prospective longitudinal study was conducted on subjects who were examined as newborns and prospectively interviewed and re-examined at 11 to 14 years old. Low birth weight (<2500 g) was present in 36% of the sample. The adolescent examination included measurements of blood pressure (BP), both auscultation and oscillometric methods; anthropometrics (height, weight, and body mass index [BMI]); health status; and health behaviors. Data were analyzed on 250 subjects. Correlation coefficients of birth weight with all BP measures were nonsignificant, except for the last auscultated diastolic BP (r=0.19, P<0.01), which had a positive relationship. The simple correlation coefficients of birth weight with adolescent body size were significant and positive for weight and BMI. After multiple linear regression analyses with adjustments for age, Tanner stage, and gestational age, there was no significant effect of birth weight on adolescent weight or BMI. No significant correlations were detected for ponderal index at birth with adolescent measures. This study, which includes a substantial portion of low-birth-weight cases (36%), indicates that birth weight does not correlate negatively with later BP. These results do not support the low-birth-weight theory and indicate that childhood factors that are more proximal have a greater effect on adolescent BP than intrauterine factors.

Overweight As a Risk Factor in Children: a Focus on Ethnicity

The prevalence of overweight in youth is increasing dramatically in the United States. The intimate relationship of obesity and overweight with cardiovascular risk factors and diabetes in adults raises concern for the likelihood of subsequent disease development in children. Ethnic minorities are so disproportionately affected by overweight that a call to action is necessary. The International Society on Hypertension in Blacks convened this work group as part of a larger effort to focus on cardiovascular risk protection beginning in childhood and adolescence, entitled the "Children are Our Messengers: Changing the Health Message" initiative. This summary article reviews the data on cardiovascular risk factors and overweight in ethnic children and adolescents, and culminates in a practical algorithm for evaluating overweight children for cardiovascular risk.

Race/ethnic Issues in Obesity and Obesity-related Comorbidities

The prevalence of obesity is increasing among all age and racial groups in the United States. There is, however, a disproportionate rise in the prevalence of obesity among African-Americans and Hispanic/Mexican Americans. Obesity is a major contributor to the insulin resistant syndrome (IRS), a condition of multiple metabolic abnormalities that is a precursor to type 2 diabetes, and confers a high risk for cardiovascular events. The estimated prevalence of IRS is also greater in Mexican Americans and African-Americans than in Caucasians. The IRS is identifiable in children, and as with adults, there are racial differences in its expression even at a young age. The obesity-associated diseases, including diabetes and hypertension, are found at higher rates within the minority races compared with Caucasians. However, there are differences, in that obesity-related hypertension occurs at higher rates among African-Americans, and obesity-related diabetes occurs at higher rates among Mexican Americans. Race/ethnic differences in lifestyle behaviors and economic disadvantage may account for some of the race disparity in obesity-related diseases and disease outcomes. Environmental factors, however, do not explain all of the race disparity in disease expression, indicating that there are genetic/molecular factors that are operational as well.

Obesity and High Blood Pressure: a Clinical Phenotype for the Insulin Resistance Syndrome in African Americans

The high prevalence of insulin resistance syndrome in African Americans predisposes this population to higher morbidity and mortality from cardiovascular disease. To test the hypothesis that the combination of obesity and high blood pressure (BP) represents the physical phenotype of insulin resistance syndrome, 337 African-American men and women aged 32+/-4 years were examined and classified into four groups (nonobese-normal BP, nonobese-high BP, obese-normal BP, obese-high BP), according to presence or absence of obesity and high BP. Mean values of glucose, insulin, lipids, urinary albumin excretion, and clamp-derived insulin sensitivity were determined for each group. Prevalence of prediabetes (24.4%), diabetes (19.2%), and insulin resistance syndrome (87.2%) were highest in the obese-high BP group (p<0.001). Mean triglycerides, urinary albumin excretion, fasting glucose, fasting insulin, and insulin resistance were highest in the obese-high BP group (p<0.001). Subjects with both obesity and high BP showed greater expression of lipid and glucose abnormalities, higher urinary albumin excretion, and greater prevalence of prediabetes, undetected type 2 diabetes, and insulin resistance syndrome.

Correlation of Oral Glucose Tolerance Test-derived Estimates of Insulin Sensitivity with Insulin Clamp Measurements in an African-American Cohort

The purpose of this study was to determine which measures obtained from an oral glucose tolerance test (OGTT) are the best estimates of insulin sensitivity measured directly using the euglycemic hyperinsulinemic clamp procedure. Data were examined from a study conducted on 307 young adult African-American men and women. An OGTT with insulin measurements was conducted after a 12-hour overnight fast. The euglycemic hyperinsulinemic clamp was used to measure insulin-stimulated glucose uptake (M) directly. Pearson's correlation analyses were performed to examine the relationship of OGTT-derived parameters with insulin sensitivity measured using the clamp. There were consistent statistically significant correlations between calculated estimates of insulin sensitivity (fasting insulin/fasting glucose, summed insulin/summed glucose, homeostasis model assessment [HOMA], Quantitative Insulin Sensitivity Check Index [QUICKI]) with insulin sensitivity measured by the insulin clamp (P <.001). The calculated estimates that correlated most strongly with clamp measured insulin sensitivity were QUICKI and the logarithm of summed insulin during the OGTT. These data indicate that fasting and OGTT-derived plasma insulin and glucose concentrations can be used to estimate insulin sensitivity in young adult African-Americans when it is not feasible to conduct the insulin clamp procedure. Calculated indices that include log transformation of plasma insulin concentration improve the estimation of insulin sensitivity.

Summary of the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents

Relationship of Homocysteine with Cardiovascular Disease and Blood Pressure

Elevated plasma homocysteine (Hcy) concentration is considered a risk factor for cardiovascular disease and may also be associated with hypertension. Although links have been established between hyperhomocysteinemia and elevated risk for cardiovascular events, the precise role of plasma Hcy in cardiovascular disease is unclear. Plasma Hcy increases with aging and is associated with other health-related behaviors, including smoking and diet patterns. Both epidemiologic and longitudinal clinical investigations have investigated the possible contribution of plasma Hcy to cardiovascular disease, and most report an association of plasma Hcy with the risk for cardiovascular and cerebral events. Some reports describe a significant relationship between Hcy and blood pressure levels, as well as higher Hcy in hypertensives compared to normotensives. Other studies find that the effect of Hcy disappears following adjustment for other risk factors. Because Hcy cosegregates with other risk factors, it has been difficult to identify an independent effect of Hcy on cardiovascular disease or hypertension. Hcy can be modified to some extent by vitamin supplementation. Hcy reduction may have some benefit in reducing cardiovascular risk in some patients, particularly the elderly. Because the question of an independent role of Hcy on risk for cardiovascular disease has not been determined, the assessment and treatment of Hcy should be approached in the context of other modifiable risk factors.

Recommendations for Blood Pressure Measurement in Humans and Experimental Animals: Part 1: Blood Pressure Measurement in Humans: a Statement for Professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research

Accurate measurement of blood pressure is essential to classify individuals, to ascertain blood pressure-related risk, and to guide management. The auscultatory technique with a trained observer and mercury sphygmomanometer continues to be the method of choice for measurement in the office, using the first and fifth phases of the Korotkoff sounds, including in pregnant women. The use of mercury is declining, and alternatives are needed. Aneroid devices are suitable, but they require frequent calibration. Hybrid devices that use electronic transducers instead of mercury have promise. The oscillometric method can be used for office measurement, but only devices independently validated according to standard protocols should be used, and individual calibration is recommended. They have the advantage of being able to take multiple measurements. Proper training of observers, positioning of the patient, and selection of cuff size are all essential. It is increasingly recognized that office measurements correlate poorly with blood pressure measured in other settings, and that they can be supplemented by self-measured readings taken with validated devices at home. There is increasing evidence that home readings predict cardiovascular events and are particularly useful for monitoring the effects of treatment. Twenty-four-hour ambulatory monitoring gives a better prediction of risk than office measurements and is useful for diagnosing white-coat hypertension. There is increasing evidence that a failure of blood pressure to fall during the night may be associated with increased risk. In obese patients and children, the use of an appropriate cuff size is of paramount importance.

Roundtable Discussion: Hypertension in Children and Adolescents

Following a hypertension symposium held in Philadelphia, PA, on June 8, 2004, a roundtable discussion was held to discuss the treatment of hypertension in adolescents and children. The participants included Thomas D. Giles, MD, of Louisiana State College of Medicine, New Orleans, LA; Bonita Falkner, MD, of the Department of Medicine and Pediatrics, Thomas Jefferson University, Philadelphia, PA; Allan B. Schwartz, MD, of the Division of Nephrology and Hypertension, Drexel University College of Medicine, Philadelphia, PA; Raymond R. Townsend, MD, of the Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA; and Marvin Moser, MD, of the Department of Medicine/Cardiology, Yale University School of Medicine, New Haven, CT.

Recommendations for Blood Pressure Measurement in Humans and Experimental Animals: Part 1: Blood Pressure Measurement in Humans: a Statement for Professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research

Accurate measurement of blood pressure is essential to classify individuals, to ascertain blood pressure-related risk, and to guide management. The auscultatory technique with a trained observer and mercury sphygmomanometer continues to be the method of choice for measurement in the office, using the first and fifth phases of the Korotkoff sounds, including in pregnant women. The use of mercury is declining, and alternatives are needed. Aneroid devices are suitable, but they require frequent calibration. Hybrid devices that use electronic transducers instead of mercury have promise. The oscillometric method can be used for office measurement, but only devices independently validated according to standard protocols should be used, and individual calibration is recommended. They have the advantage of being able to take multiple measurements. Proper training of observers, positioning of the patient, and selection of cuff size are all essential. It is increasingly recognized that office measurements correlate poorly with blood pressure measured in other settings, and that they can be supplemented by self-measured readings taken with validated devices at home. There is increasing evidence that home readings predict cardiovascular events and are particularly useful for monitoring the effects of treatment. Twenty-four-hour ambulatory monitoring gives a better prediction of risk than office measurements and is useful for diagnosing white-coat hypertension. There is increasing evidence that a failure of blood pressure to fall during the night may be associated with increased risk. In obese patients and children, the use of an appropriate cuff size is of paramount importance.

Recommendations for Blood Pressure Measurement in Humans: an AHA Scientific Statement from the Council on High Blood Pressure Research Professional and Public Education Subcommittee

Effect of Obesity and High Blood Pressure on Plasma Lipid Levels in Children and Adolescents

To examine the extent of blood lipid abnormalities in overweight children and to determine whether the prevalence of dyslipidemia is different in overweight children with elevated blood pressure (BP) compared with overweight children with normal BP (NBP).

The Metabolic Syndrome--what is It and How Should It Be Managed?

Following a hypertension symposium in Portland, ME, in October 2005, a roundtable was convened to discuss the metabolic syndrome and its significance. Dr. Marvin Moser of the Yale University School of Medicine, New Haven, CT, moderated the discussion. Participating in the discussion were Dr. Bonita Falkner of the Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA; Dr. Michael A. Weber of SUNY Downstate College of Medicine, New York, NY; and Dr. Leonard Mark Keilson of the University of Vermont College of Medicine.

The Relationship of Body Mass Index and Blood Pressure in Primary Care Pediatric Patients

To determine whether an association of overweight, or risk of overweight, and blood pressure can be detected in children in the pediatric primary care practice setting.

The Utility of Fasting Glucose for Detection of Prediabetes

Treatment of prediabetes attenuates progression to type 2 diabetes mellitus. The American Diabetes Association (ADA) previously defined prediabetes as either impaired fasting glucose (IFG) = 6.1 to 6.9 mmol/L (110-125 mg/dL) and/or impaired glucose tolerance (IGT) (2-hour postload glucose of 7.8-11.0 mmol/L [140-199 mg/dL]). For practical reasons, fasting plasma glucose (FPG) is commonly used for diabetes screening. Recently, the ADA lowered the fasting glucose threshold value for IFG from 110 to 100 mg/dL. Our objective was to determine the utility of FPG alone for detecting prediabetes in African Americans. Oral glucose tolerance test (OGTT) data from a cohort of 304 young adult African American men and women were examined. We calculated prediabetes prevalence using the previous ADA criteria and examined the effect of lowering the IFG threshold value for IFG to 100 mg/dL. The prediabetes prevalence in this cohort using the previous ADA criteria was 20.4% (n = 62). Of the 62 cases, 8 had IFG, 45 had IGT, and 9 had IFG together with IGT. Fasting plasma glucose testing alone detected 17 (27.4%) prediabetic cases, whereas a complete OGTT detected 54 (87.1%). Lowering the IFG threshold value to FPG = 100 mg/dL identified 13 of the 45 IGT-only cases. However, this lower IFG threshold increased prediabetes prevalence in the overall cohort from 20.4% to 31.9%. In conclusion, in young adult African Americans, an ethnic group at high risk for developing diabetes, FPG testing alone may be inadequate for diagnosing prediabetes. Until alternative strategies are identified, an OGTT is presently the best method for detecting the prediabetic condition in these high-risk patients.

Metoprolol Succinate, a Selective Beta-adrenergic Blocker, Has No Effect on Insulin Sensitivity

Insulin resistance is a risk factor for cardiovascular disease. Therapies to lower blood pressure should not decrease insulin sensitivity. Some b-adrenergic blocking agents can have an adverse effect on insulin sensitivity. This study examined the effect of extended-release metoprolol succinate on insulin sensitivity. Nondiabetics with hypertension (N=30) were started on (or changed to) hydrochlorothiazide (HCTZ) 12.5 mg daily for 14 days. Patients with blood pressure>140/90 mm Hg while taking HCTZ alone underwent an insulin clamp procedure to quantify insulin sensitivity. Metoprolol succinate treatment was begun at 50 mg daily and titrated to a dose that lowered blood pressure to <140/90 mm Hg. Following 12 weeks of metoprolol succinate plus HCTZ therapy, the insulin clamp procedure was repeated. On metoprolol succinate plus HCTZ treatment, there were no significant changes in insulin clamp measures of insulin sensitivity. Plasma cholesterol and low-density lipoprotein cholesterol decreased significantly on metoprolol succinate plus HCTZ. When b-blocker therapy is considered, metoprolol succinate can be used to treat hypertension without adverse metabolic effects.

Hypertension in Children

Essential, or primary, hypertension is detectable in childhood. Due to the rising rates of childhood obesity, the expression of essential hypertension in childhood is increasing. Despite this trend, the possibility of secondary hypertension should be considered in a child with documented hypertension. Children and adolescents with suspected secondary hypertension may require a more extensive evaluation compared with those expressing characteristics of essential hypertension. Whether the hypertension is determined to be secondary or essential, these children require careful monitoring, interventions to control the blood pressure, and long-term follow-up. Considering the long-term morbidity and mortality associated with essential hypertension, interventions, including preventive interventions, that focus on blood pressure control beginning in the young are an important component of healthcare for children and adolescents.

Metabolic Disease in Childhood

Association of Age and Sex with Cardiovascular Risk Factors and Insulin Sensitivity in Overweight Children and Adolescents

To determine the effect of age and sex on cardiovascular risk factor expression in overweight children, data from clinical records of 497 overweight children (2-18 years of age) were examined. Data included average blood pressure (BP), fasting lipids, glucose, and insulin. The sample was stratified by age (younger than 11 and 11 years and older) and analyzed by sex. Subjects with an average BP > or = 90th percentile were classified as having high BP. Insulin and glucose were used in equations to estimate insulin sensitivity. Among subjects 11 years and older (n = 268), 52.6% of males had high BP compared with 32.6% of females (P < .001). Mean high-density lipoprotein cholesterol was lowest in the males 11 years and older compared with the females and younger males (P < .01). Triglyceride levels trended higher in males independent of age. In multivariate analyses, high BP was most strongly associated with age and severity of overweight while triglyceride level was most associated with sex and insulin resistance. The prevalence of high BP and dyslipidemia in overweight children is high. Overweight males 11 years and older have a higher prevalence of high BP and low high-density lipoprotein cholesterol than females and younger males. Greater cardiovascular risk factor expression in overweight males 11 years and older may explain the earlier appearance of cardiovascular disease end points in overweight men.

Stimulation of Urinary TGF-beta and Isoprostanes in Response to Hyperglycemia in Humans

TGF-beta and oxidant stress have been considered to play key roles in the pathogenesis of diabetic vascular complications; however, the stimulus for these factors in humans is not clear. The purpose of this in vivo study was to determine whether transient hyperglycemia in humans is sufficient to increase renal production of TGF-beta1 and urinary isoprostanes in normal humans. A hyperglycemic clamp procedure was performed on 13 healthy volunteers. An infusion of glucose was delivered to maintain the plasma glucose between 200 and 250 mg/dl for 120 min. Timed urine samples, collected on an overnight period before the study, at each void on completion of the procedure, and the following overnight, were assayed for TGF-beta1, F2-isoprostanes, and creatinine. Plasma samples were assayed for TGF-beta1 before and at timed intervals throughout hyperglycemia. Mean baseline TGF-beta1 in plasma was 4.57 +/- 0.22 ng/ml, and no change in plasma TGF-beta1 levels was detected throughout the hyperglycemia period. Baseline urine TGF-beta1 was 4.14 +/- 1.16 pg/mg creatinine. The fractional urine samples showed a sharp increase in TGF-beta1 excretion in the 12-h period after exposure to hyperglycemia, with a mean peak TGF-beta1 of 30.43 +/- 8.05 pg/mg (P = 0.002). TGF-beta1 excretion in the subsequent overnight urine sample was not different from baseline (4.62 +/- 1.21 pg/mg). Urinary isoprostanes increased from a baseline of 4.92 +/- 0.74 to 13.8 +/- 3.37 ng/mg creatinine. It is concluded that 120 min of hyperglycemia in normal humans is sufficient to induce an increase in renal TGF-beta1 and isoprostane production.

Efficacy and Safety of Extended Release Metoprolol Succinate in Hypertensive Children 6 to 16 Years of Age: a Clinical Trial Experience

To evaluate the efficacy, tolerability, and blood pressure (BP) lowering effect of extended release metoprolol succinate (ER metoprolol) in children 6 to 16 years of age with established hypertension.

Plasma Lipid Concentrations in Nondiabetic African American Adults: Associations with Insulin Resistance and the Metabolic Syndrome

Despite higher rates of cardiovascular disease, African Americans have a more favorable lipid profile. The purpose of the study was to examine the association between plasma lipid concentrations and insulin resistance in African Americans and to determine if insulin resistance is present at a lower triglyceride (TG) threshold than is used for metabolic syndrome criteria. Data were examined on 185 nondiabetic African American men (n = 61) and women (n = 124), mean age, 39.8 years. Measurements included blood pressure, anthropometrics, oral glucose tolerance test, and insulin sensitivity (M) by insulin clamp. The relationship between lipids and insulin sensitivity was analyzed by correlation analysis and by comparing TG levels among tertiles of M. Despite relatively low mean (+/- SD) TG level (87.8 +/- 55.2 mg/dL), there were statistically significant correlations of M with TG (r = -0.23, P < .002), high-density lipoprotein cholesterol (HDL-C; r = 0.19, P < .01), and TG/HDL-C ratio (r = -0.23, P < .002). The correlations were strongest in men. Subjects with TG in an intermediate range (110-149 mg/dL) had insulin resistance equivalent to that of the high-TG group (>/=150 mg/dL). In African Americans, TG levels below the current metabolic syndrome threshold criterion are associated with insulin resistance.

What Exactly Do the Trends Mean?

Androgen Excess is Associated with Insulin Resistance and the Development of Diabetes in African American Women

This study investigated the role of relative androgen excess, designated by low sex hormone-binding globulin (SHBG), on development of type 2 diabetes in premenopausal African American women. A prospective, longitudinal study was conducted on premenopausal African American women, initially aged 36 to 43 years (n=119). Patients were reexamined 8 years later to determine whether initial androgen status was associated with insulin resistance and development of diabetes. Among patients in the low SHBG tertile, 18% converted to type 2 diabetes by the second examination, as compared with 5% in the mid SHBG tertile and 2.5% in the high SHBG tertile (P=.04). Insulin sensitivity was significantly different among the 3 tertiles (P<.01). There was no significant difference in total cholesterol, high-density lipoprotein, low-density lipoprotein, or triglycerides among the SHBG tertiles. This prospective study demonstrates that relative androgen excess is associated with insulin resistance and increases the risk for development of diabetes in premenopausal African American women.

Treatment with Metoprolol Succinate, a Selective Beta Adrenergic Blocker, Lowers Blood Pressure Without Altering Insulin Sensitivity in Diabetic Patients

Insulin resistance is a risk factor for cardiovascular disease. Therapies to lower blood pressure should not decrease insulin sensitivity, especially among high-risk patients such as diabetics. This study examined the effect of the beta1-selective adrenergic receptor-blocking agent extended-release metoprolol succinate (ER metoprolol) on insulin sensitivity in type 2 diabetic patients with suboptimal blood pressure control. Diabetic patients with average blood pressure levels >130/85 mm Hg despite antihypertensive therapy had insulin sensitivity quantified by insulin clamp. ER metoprolol was then added to their ongoing therapy. Following 12 weeks of ER metoprolol plus other therapy, the insulin clamp study was repeated. There were no significant changes in measures of insulin sensitivity, plasma lipids, or hemoglobin A1c with use of ER metoprolol. When beta-blocker therapy is considered, it appears that this agent can be used to treat hypertension without adverse effects on insulin sensitivity in patients with type 2 diabetes, at least over the period of time treated.

Resistant Hypertension: Diagnosis, Evaluation, and Treatment. A Scientific Statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research

Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder.

Adiponectin Regulates Albuminuria and Podocyte Function in Mice

Increased albuminuria is associated with obesity and diabetes and is a risk factor for cardiovascular and renal disease. However, the link between early albuminuria and adiposity remains unclear. To determine whether adiponectin, an adipocyte-derived hormone, is a communication signal between adipocytes and the kidney, we performed studies in a cohort of patients at high risk for diabetes and kidney disease as well as in adiponectin-knockout (Ad(-/-)) mice. Albuminuria had a negative correlation with plasma adiponectin in obese patients, and Ad(-/-) mice exhibited increased albuminuria and fusion of podocyte foot processes. In cultured podocytes, adiponectin administration was associated with increased activity of AMPK, and both adiponectin and AMPK activation reduced podocyte permeability to albumin and podocyte dysfunction, as evidenced by zona occludens-1 translocation to the membrane. These effects seemed to be caused by reduction of oxidative stress, as adiponectin and AMPK activation both reduced protein levels of the NADPH oxidase Nox4 in podocytes. Ad(-/-) mice treated with adiponectin exhibited normalization of albuminuria, improvement of podocyte foot process effacement, increased glomerular AMPK activation, and reduced urinary and glomerular markers of oxidant stress. These results suggest that adiponectin is a key regulator of albuminuria, likely acting through the AMPK pathway to modulate oxidant stress in podocytes.

Resistant Hypertension: Diagnosis, Evaluation, and Treatment: a Scientific Statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research

Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder.

Blood Pressure Variability and Classification of Prehypertension and Hypertension in Adolescence

There is little information in pediatrics on the persistence of the prehypertension and hypertension classifications or on the progression of prehypertension to hypertension. This study aimed to examine those issues.

Birth Weight and Risk of Type 2 Diabetes: a Systematic Review

Low birth weight is implicated as a risk factor for type 2 diabetes. However, the strength, consistency, independence, and shape of the association have not been systematically examined.

Capillary Rarefaction in Treated and Untreated Hypertensive Subjects

This study aimed to determine if capillary rarefaction is detectable and associated with endothelial dysfunction in persons with mild systolic blood pressure (SBP) elevation. Capillary density and endothelial function were quantified for 150 nondiabetic participants, grouped by blood pressure (BP) as normotensive, untreated high BP, and treated high BP. Structural capillary rarefaction measures were not different between the three groups. Functional capillary rarefaction measures were significantly lower in both high BP groups compared to normotensives, and correlated inversely with endothelial function. The study findings indicate that the hypertensive vascular pathologic process is already underway at modest levels of blood pressure elevation.

Functional Capillary Rarefaction in Mild Blood Pressure Elevation

Capillary rarefaction is described in patients with moderate to severe hypertension. The study objective was to determine if structural and/or functional capillary rarefaction is detectable and associated with endothelial dysfunction in patients with mild blood pressure elevation (HBP: Systolic blood pressure 130 - 160 mm Hg). Capillary density was quantified by direct capillaroscopy in 110 nondiabetic black and non-black subjects. Endothelial function was quantified by plethysmographic measures of flow-mediated vasodilation. Compared to normotensives (NBP: N = 90), functional capillary rarefaction was detected in HBP (N = 20; P<0.001). Functional capillary density measures correlated with endothelial function (P<0.001). Functional, but not structural, capillary rarefaction is detectable and associated with endothelial dysfunction in both black and non-black individuals with mild blood pressure elevation.

Children and Adolescents with Obesity-associated High Blood Pressure

Hypertension and obesity are both common health problems in children and adolescents. More than 17% of children are obese and even more children are overweight. Hypertension, although defined differently in children than in adults, can be detected in 3% to 4% of children, and approximately 30% of obese adolescents have high blood pressure (BP) associated with obesity. Children with high BP and obesity frequently have other risk factors that are components of the metabolic syndrome. Evidence of target organ damage, including left ventricular hypertrophy, is detectable in many children with hypertension and is more commonly found in children with high BP and obesity. Both obesity and hypertension are considered inflammatory conditions. There are some emerging data in the young that show an association of insulin resistance, obesity, and high BP with inflammatory markers. Children and adolescents with hypertension and especially obesity-associated hypertension can be identified and should be evaluated for additional metabolic risk factors. Considering the heightened risk for premature cardiovascular (CV) disease, therapeutic interventions, including lifestyle changes and medications, when indicated, are important for all children and adolescents with obesity-associated hypertension.

Association of a Polymorphic Variant of the Adiponectin Gene with Insulin Resistance in African Americans

Hypertension, type 2 diabetes, and obesity are common complex disorders that contribute to cardiovascular (CV) disease. Insulin resistance increases CV risk and is present in these disorders. Adiponectin, a protein secreted by adipocytes with metabolic and vascular protective effects, is lower in obesity and insulin resistance. Several single nucleotide polymorphisms (SNP) have been identified in the adiponectin (ADIPOQ) gene. Associations of ADIPOQ polymorphisms with diabetes and obesity have been described in Caucasians and Asians. The purpose of this study was to determine if genetic variants of ADIPOQ are associated with insulin resistance and CV risk in African Americans. Metabolic traits (lipids, glucose, insulin, and insulin sensitivity) and blood pressure were measured in 273 African Americans. DNA was examined by DNA sequence analysis and SNPs of candidate genes including ADIPOQ were studied. Statistica analyses were performed by regression of the quantitative trait phenotypes on the groups defined by the SNP genotypes, adjusting for age, sex, and body mass index (BMI). SNP 712 (rs3774261) ofthe/lD/POQgene showed significant association with insulin resistance (p= 0.001). Despite the relatively small sample, our results indicate that genes that regulate adipocyte function may have a regulatory role in the expression of metabolic traits in obesity-associated chronic disease.

Parental Assessments of Internalizing and Externalizing Behavior and Executive Function in Children with Primary Hypertension

To determine the relations between hypertension and parental ratings of behavior and executive functions in children with primary hypertension and to examine the potential moderating influence of obesity.

Insulin Resistance Predicts Future Deterioration of Glucose Tolerance in Nondiabetic Young African Americans

Insulin resistance has been linked to the development of type 2 diabetes mellitus and increased cardiovascular risk in several high-risk populations. The purpose of this study was to determine if insulin resistance measured by insulin clamp can predict deterioration of glucose metabolism and increased cardiovascular risk in nondiabetic young adult African Americans. Nondiabetic young African American men (n = 60) and women (n = 114) were enrolled. Measurements obtained included blood pressure, anthropometrics, plasma lipids, oral glucose tolerance test, and insulin sensitivity by insulin clamp. Participants were reexamined 8 years later. The relationship between insulin sensitivity and glucose metabolism was analyzed using a 2-way analysis of variance with body mass index at the initial examination as a covariate. After adjusting for the significant difference of body mass index between the insulin-resistant and insulin-sensitive groups, insulin resistance predicted statistically significant worsening glucose metabolism, developing diabetes, and increasing risk factors for cardiovascular disease.

Refining the Blood Pressure Phenotype in Children: when Does Target Organ Damage Begin?

G Protein-coupled Receptor Kinase 2 Expression and Activity Are Associated with Blood Pressure in Black Americans

Hypertension occurs with higher prevalence and morbidity in black Americans compared with other groups. Alterations in the signal transduction pathways of 7-transmembrane spanning receptors are found in hypertensive patients. G protein-coupled receptor kinases (GRKs) play an important role in regulating this receptor signaling. The 2 most abundantly expressed GRKs in the cardiovascular system are GRK2 and GRK5, and each has unique substrates. Understanding changes in expression may give us insight into activated receptors in the pathophysiological progression of hypertension. In heart failure and white hypertensives, increased GRK2 expression arises because of neurohormonal stimulation of particular receptors. GRK2 subsequently desensitizes specific receptors, including beta-adrenergic receptors. In blood pressure control, beta-adrenergic receptor desensitization could lead to increased blood pressure. GRK2 and GRK5 mRNA were evaluated in lymphocytes of black Americans via quantitative real-time PCR. GRK2 mRNA expression directly correlated with systolic blood pressure and norepinephrine levels. GRK2 was elevated >30% among those with systolic blood pressure > or =130 mm Hg. No significant correlation between GRK5 mRNA expression and blood pressure or catecholamines was observed. Diabetic status, age, sex, and body mass index were also compared with GRK2 expression using univariate and multivariate analyses. GRK2 protein expression was elevated 2-fold in subjects with higher blood pressure, and GRK activity was increased >40%. Our data suggest that GRK2, but not GRK5, is correlated with increasing blood pressure in black Americans. Understanding the receptors stimulated by increased neurohormonal activation may give insight into the pathophysiology of hypertension in this at-risk population.

Should the Current Approach to the Evaluation and Treatment of High Blood Pressure in Children Be Changed?

The Importance of Blood Pressure Screening in Children

Blood Pressure Differences by Ethnic Group Among United States Children and Adolescents

Large differences in blood pressure (BP) by ethnic group are apparent among adults. There is uncertainty as to whether similar differences by ethnic group exist among children and, if so, the age of onset. BP measurements were obtained from 58 698 children at 78 556 visits using Pediatric Task Force data, a collection of 11 studies with BP data from children and adolescents age 1 to 17 years. Generalized estimating equation methods were used to identify sex-specific differences in body mass index (BMI)-adjusted rates of BP elevation and prehypertension by ethnic group. Significant BMI-adjusted differences in rates of BP elevation were found between Hispanic boys versus white boys (odds ratio: 1.21; 95% CI: 1.07 to 1.37; P=0.002). No overall significant differences were found between black boys versus white boys (odds ratio: 1.03; 95% CI: 0.95 to 1.12; P=0.49); however, there was significant effect modification (P=0.01) with significant differences found for normal-weight boys (BMI: <85th percentile; OR black versus white: 1.14; 95% CI: 1.03 to 1.27; P=0.01) but not for overweight boys (BMI: > or =85th percentile; OR black versus white: 0.90; 95% CI: 0.78 to 1.05; P=0.20). No overall ethnic group differences in BMI-adjusted rates of hypertension were found for girls. Ethnic differences in prevalence rates of pediatric BP elevation that are not explained by obesity are present, primarily in boys. Whether these differences are attributable to genetic or environmental factors is unknown.

Hypertension in Children and Adolescents: an Approach to Management of Complex Hyper-tension in Pediatric Patients

Although primary (essential) hypertension is detectable in childhood, secondary causes of hypertension must be considered in evaluating and managing hypertension in children and adolescents. Very young children and children with severe hypertension may have an underlying cause of the hypertension. Interventions to control elevated blood pressure (BP) are clinically important for all children with high BP. Nonpharmacologic approaches are recommended for all asymptomatic children with hypertension and prehypertension. Some children and adolescents will require pharmacologic therapy to control BP and to optimize organ protection. Recent advancements in pediatric clinical trials of antihypertensive agents have provided data on BP-lowering effects and safety in children. Little has been published on the choice and use of various classes of antihypertensive drugs for management of secondary hypertension in children and adolescents. This review focuses on the clinical management of specific types of secondary hypertension in pediatric patients.

Hypertension in Children and Adolescents: Epidemiology and Natural History

Primary hypertension is detectable in children and adolescents and, as in adults, is associated with a positive family history of hypertension, obesity, and life-style factors. Owing to the well-established childhood obesity epidemic, the population prevalence of high blood pressure (BP) in the young is increasing. Hypertension in childhood is commonly associated with other cardiovascular risk factors as well as obesity. Although death and cardiovascular disability do not occur in hypertensive children, intermediate markers of target organ damage, such as left ventricular hypertrophy, thickening of the carotid vessel wall, retinal vascular changes, and even subtle cognitive changes, are detectable in children and adolescents with high BP. Considering the rates of verified hypertension (>3%) and pre-hypertension (>3%) in asymptomatic children and adolescents, high BP should be considered a common long-term health problem in childhood.

Association of Capillary Density and Function Measures with Blood Pressure, Fasting Plasma Glucose, and Insulin Sensitivity

The pathophysiology underlying the association between hypertension and insulin resistance remains unclear. The study purpose was to determine whether reduced capillary density and/or function underlie, and may therefore explain, this association. The study was conducted on 115 black and non-black participants aged 18 to 55 years: 91 with normal blood pressure (systolic blood pressure [SBP] <130 mm Hg) and 24 with mild blood pressure elevation (SBP 130-159 mm Hg). Capillary density and function were quantified using direct capillaroscopy measures. Insulin sensitivity (IS) was estimated using the Quantitative Insulin Sensitivity Check Index (QUICKI). Endothelial function (EF) was measured using strain-gauge plethysmography. Data were analyzed by linear regression adjusted for age, sex, race, and body mass index (BMI). After adjustment for BMI, capillary density and function measures were significant predictors of SBP ( P<.01), fasting plasma glucose (P=.012, P=.03, and P=.004, respectively), and EF (P=.033, P=.001, and P=.009, respectively). However, none of the capillary measures were significant predictors of fasting insulin or IS. These capillaroscopy data demonstrated an association with SBP but not insulin resistance, suggesting that capillary measures are unlikely to explain the association between hypertension and insulin resistance, at least with modest degrees of blood pressure elevation.

Parental Assessment of Executive Function and Internalizing and Externalizing Behavior in Primary Hypertension After Anti-hypertensive Therapy

To determine the change in parental ratings of executive function and behavior in children with primary hypertension after anti-hypertensive therapy.

Regulation of Transforming Growth Factor-beta1 by Insulin in Prediabetic African Americans

Insulin resistance has been associated with kidney disease even in the absence of diabetes; however, pathways linking insulin resistance to kidney disease are unclear. The purpose of this study was to determine if transforming growth factor (TGF)-beta1, a key cytokine associated with kidney disease, responds to circulating levels of glucose and/or insulin. Urinary TGF-beta1 levels were measured in 249 young adult African Americans (mean age 40) at baseline, after an oral glucose tolerance test and after a euglycemic hyperinsulinemic clamp procedure. Baseline urinary geometric mean TGF-beta1 levels were somewhat lower in those with normal compared with the impaired glucose tolerance. The urinary TGF-beta1 level increased by 56% followed by a 23% decrease in the normal glucose tolerance group, changes that were significant and corresponded to the changes in the plasma glucose and insulin concentrations. The impaired tolerance group showed little change in the urinary TGF-beta1 level following glucose ingestion. All participants had a significant increase in urinary TGF-beta1 level after steady-state hyperinsulinemia, with sustained euglycemia during the clamp procedure in both of the groups. At baseline, there was a significant correlation between the urinary TGF-beta1 level and urinary albumin excretion. Thus our results suggest that insulin contributes to increased TGF-beta1 production and possible early renal injury in prediabetic young African Americans.

High Blood Pressure in Children: Clinical and Health Policy Implications

Hypertension is a global problem, affecting both developed and developing nations. In addition to being a major cause of morbidity and mortality, hypertension places a heavy burden on health care systems, families, and society as a whole. Despite evidence of an increasing prevalence of hypertension among youth, the consequences of early onset are poorly established and often overlooked. Childhood hypertension is often asymptomatic and easily missed, even by health professionals. Target organ damage is detectable in children and adolescents, however, and hypertension continues into adulthood. Additional strategies to improve cardiovascular health among children and adolescents are needed, including methods to achieve healthy lifestyles at home and in school, improved systems for diagnosis, and research on mechanisms and timing of interventions. The burden of hypertension in the young will continue to grow unless it is given the attention it deserves by policy makers, health care providers, schools, parents, and society. This report aims to increase awareness of the problem of hypertension in childhood. Recent reports on prevalence and target organ injury are discussed and health policy initiatives to improve blood pressure control are proposed.

Alterations in Capillary Morphology Are Found in Mild Blood Pressure Elevation

Remodeling of small resistance arteries is an early sign of target organ damage in hypertension. Peripheral capillary morphology abnormalities in hypertension are not well studied. The study objective was to determine whether altered capillary morphology is associated with SBP, DBP, or both in individuals without and with mild blood pressure elevation (SBP = 130-160 mmHg). Another objective was to determine whether capillary morphology is associated with minimum forearm vascular resistance, a measure of altered resistance artery structure.

Endothelin-1 Response to Glucose and Insulin Among African Americans

Endothelin-1 (ET-1) is implicated in the pathogenesis of hypertension. In vitro studies demonstrate that ET-1 is upregulated by insulin and glucose. The purpose of this study was to determine the effects of insulin and glucose on ET-1 levels in young adult African Americans, a population with a high burden of hypertension and diabetes. Plasma and urine ET-1 levels were measured before and after an oral glucose tolerance test (OGTT) and insulin clamp procedure in 288 participants. Subjects were classified according to glucose tolerance and blood pressure (BP) status. Plasma and urine ET-1 were not significantly different among the glucose tolerance groups. There was a trend toward increased plasma ET-1 among those with diabetes compared with impaired glucose tolerance and normal glucose tolerance; however, this was not statistically significant (P = .085). According to BP status, plasma ET-1 was highest among the high BP group compared with the normal BP group (P = .01). After glucose challenge, plasma ET-1 levels decreased and urine ET-1 increased in all three BP groups (P = .037). Our data show that plasma ET-1 is higher among young adult African Americans with hypertension compared with normotension. Urine ET-1 levels increased in response to glucose challenge, possibly indicating early renal injury.

A Web-based Patient Activation Intervention to Improve Hypertension Care: Study Design and Baseline Characteristics in the Web Hypertension Study

Despite the known health risks of hypertension, many hypertensive patients still have uncontrolled blood pressure. Clinical inertia, the tendency of physicians not to intensify treatment, is a common barrier in controlling chronic diseases. This trial is aimed at determining the impact of activating patients to ask providers to make changes to their care through tailored feedback.

Relationships of Total Adiponectin and Molecular Weight Fractions of Adiponectin with Free Testosterone in African Men and Premenopausal Women

Adiponectin, a protein secreted by adipose tissue, has anti-inflammatory, antithrombogenic, and antidiabetogenic effects. Lower plasma adiponectin levels are present in diabetes, obesity, and the metabolic syndrome. Adiponectin levels are higher in women compared with men. The purpose of this study was to determine whether there is a relationship between total adiponectin, or the molecular weight fractions of adiponectin, and testosterone levels in African American men and premenopausal women. A sample (N=48) of men and premenopausal women was selected based on high and low serum-free testosterone level. All patients had data on blood pressure, metabolic risk factors, and sex hormone levels. Stored plasma samples were assayed for total adiponectin. Molecular weight fractions of adiponectin were separated by gel electrophoresis and quantified by Western blot. Data analysis compared adiponectin (total and fractions) levels with androgen status in both sexes. Among men with high testosterone levels, all fractions of adiponectin were significantly lower than those in men with low testosterone (P<.05). In women with high testosterone, total adiponectin (P=.02) and all fractions of molecular weight adiponectin (P<.05) were lower compared with those in women with low testosterone. Plasma adiponectin levels are lower in both men and premenopausal women with relatively higher testosterone levels.

Variants in Genes Involved in Functional Pathways Associated with Hypertension in African Americans

Essential hypertension (HBP) is a complex trait with a substantial heritable component. The purpose of this study was to determine if variants in the G-protein coupled receptor Kinase-4 (GRK4), nitric oxide synthase-3 (NOS3), or angiotensin converting enzyme (ACE) genes are associated singly or through complex interactions, with HBP in African Americans aged 18-49 years. TaqMan Assays were used for genotyping the GRK4 and NOS3 variants. The ACE I/D variant was obtained by polymerase chain reaction and electrophoresis. Allelic association tests were performed for the five markers using PLINK. Logistic regression models were fitted to investigate associations between HBP status and the genetic markers. Multilocus analyses were also conducted. The study included 173 hypertensives and 239 normotensives, with stratification into obese and nonobese groups. The GRK4 A486V variant was negatively associated with HBP in the nonobese group (p = 0.048). The TT/CT genotype of GRK4 A486V was associated with decreased risk for HBP relative to the CC genotype after adjusting for age, sex, and body mass index (p = 0.028). Individuals having at least one NOS3 A allele and GRK4 R65L genotype GG had odds of HBP of 2.97 relative to GG homozygotes for NOS3 and GRK4 R65L. These results show very modest effects and do not fully replicate previous studies.

Insulin Resistance and Metabolic Syndrome in Prepubertal Boys with Klinefelter Syndrome

To investigate risk factors for metabolic syndrome in prepubertal boys with Klinefelter syndrome.

Relationship of Adipokines with Insulin Sensitivity in African Americans

Cytokines produced by adipose tissue, including adiponectin, have been associated with metabolic abnormalities. The purpose of this study was to examine the relationship of insulin sensitivity measured by euglycemic hyperinsulinemic insulin clamp with plasma adiponectin and other adipokines in young adult African Americans.

Pirfenidone for Diabetic Nephropathy

Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebo-controlled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m²). The prespecified primary outcome was a change in eGFR after 1 year of therapy. We randomly assigned 26 subjects to placebo, 26 to pirfenidone at 1200 mg/d, and 25 to pirfenidone at 2400 mg/d. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200-mg/d group (+3.3 ± 8.5 ml/min per 1.73 m²) whereas the mean eGFR decreased in the placebo group (-2.2 ± 4.8 ml/min per 1.73 m²; P = 0.026 versus pirfenidone at 1200 mg/d). The dropout rate was high (11 of 25) in the pirfenidone 2400-mg/d group, and the change in eGFR was not significantly different from placebo (-1.9 ± 6.7 ml/min per 1.73 m²). Of the 77 subjects, 4 initiated hemodialysis in the placebo group, 1 in the pirfenidone 2400-mg/d group, and none in the pirfenidone 1200-mg/d group during the study (P = 0.25). Baseline levels of plasma biomarkers of inflammation and fibrosis significantly correlated with baseline eGFR but did not predict response to therapy. In conclusion, these results suggest that pirfenidone is a promising agent for individuals with overt diabetic nephropathy.

Obesity Hypertension in Adolescents: Epidemiology, Evaluation, and Management

The prevalence of hypertension among all adolescents is approximately 3.5%, with somewhat higher rates of prehypertension. Obesity affects approximately 20% of adolescents in the United States, and the prevalence of hypertension is much higher among obese adolescents compared with nonobese adolescents. As in other populations, the evaluation of elevated blood pressure in obese adolescents should begin with a confirmation of the blood pressure elevation, followed by a focused diagnostic work-up to detect possible secondary causes of hypertension. Primary therapy for obesity-related hypertension in adolescents begins with weight loss, and may include antihypertensive medications if target-organ damage or other indications for drug therapy are present. The emphasis of management should be reduction of future cardiovascular risk.

Relationship of Blood Pressure and Obesity with Inflammatory Cytokines Among African Americans

Hypertension and obesity are major public health issues. Both conditions are highly prevalent among African Americans and contribute to the increased burden of cardiovascular disease in this group. Inflammation is considered to be an underlying process in both conditions. The authors sought to determine if there is an interaction between high blood pressure (HBP) and obesity that is associated with markedly elevated plasma levels of proinflammatory cytokines in African American adults.

High Blood Pressure and Obesity Increase the Risk of Abnormal Glucose Tolerance in Young Adult African Americans

Higher prevalence of both hypertension and obesity in African Americans is associated with a disproportionately greater burden of cardiovascular diseases in this ethnic group. The purpose of this study was to examine whether there is an interaction between hypertension and obesity that significantly increases the expression of metabolic risk factors for cardiovascular disease. Four groups of young adult African Americans were recruited based on their weight and blood pressure (BP). The effects of weight and BP on metabolic risk factors were analyzed based on data obtained from 484 patients. Results demonstrated that high BP and obesity were independently associated with increased odds of abnormal glucose tolerance, 1.8- and 2.2-fold, respectively. The coexistence of both high BP and obesity further increased the odds of abnormal glucose tolerance 4-fold. In addition, the geometric mean of homeostasis model assessment, an estimate of insulin resistance, increased by 18% with high BP, 60% with obesity, and 90% with the presence of both high BP and obesity. Although no statistically significant interaction between high BP and obesity was detected, the relationships of both high BP and obesity with metabolic risk factors were clearly additive.

Childhood Obesity and Blood Pressure: Back to the Future?

Central Blood Pressures Are Associated with Left Ventricular Mass Index Among African-American Adolescents

There is a high burden of premature cardiovascular disease (CVD) among African Americans. Measures of central aortic blood pressure (CASP) and wave reflection are predictive of CVD risk in adults, but there is a paucity of data regarding the relation of these measures to target organ damage among adolescents. The objective of this study was to examine the relationship between CASP, central pulse pressure (CPP), and augmentation index (AI) with left ventricular mass index (LVMI).

Prehypertension in Adolescents: How High is the Risk for Hypertension?

Aldosterone and Aldosterone: Renin Ratio Associations with Insulin Resistance and Blood Pressure in African Americans

African Americans have more hypertension and hypertension-related morbidity than whites. Aldosterone, in presence of a high salt intake, contributes to hypertension and tissue injury. Inappropriately elevated aldosterone levels could explain this racial disparity. Our study was conducted to determine if aldosterone is associated with elevated blood pressure (BP) or insulin resistance, independent of obesity. A study was conducted on 483 young adult African Americans without cardiovascular or renal disease. Measurements included anthropometrics, BP, lipids, glucose, insulin, aldosterone, and renin. Urine sodium and potassium estimated sodium intake. The cohort was stratified by tertiles of aldosterone and tertiles of aldosterone/renin ratio (ARR). Average urine sodium/potassium ratio was >3.0 in all groups. Insulin resistance, estimated by homeostasis model, was lowest in the low aldosterone group (geometric mean 1.5 [0.6, 2.2]) compared with the high aldosterone group (1.7 [0.9, 2.7], P < .01). Adjusted analyses detected a significant association of aldosterone with insulin resistance, independent of other variables. BP was significantly higher in the high ARR group compared with low and mid ARR groups (P < .01). The significant association of ARR with BP with high dietary sodium suggests that insufficiently suppressed aldosterone may contribute to BP sensitivity to sodium in African Americans.

Recent Advances in Pediatric Hypertension

Progression of Prehypertension to Hypertension in Adolescents

In the 2004 report from the National High Blood Pressure (BP) Education Program Working Group on BP in Children and Adolescents, the term "high normal BP" was replaced with the designation "prehypertension". It was proposed that BP levels that were higher than normal but did not reach the level of hypertension posed an increased risk for progression to hypertension. The overall intent of this description was to help identify children who were at the greatest risk for the development of hypertension. These are children and adolescents for whom targeted prevention programs are expected to be most beneficial. Following the 2004 report, the prehypertension condition has been examined and described in adolescents as well as adults. This review summarizes the knowledge that has been gained on prehypertension including clinical characteristics, rates of progression to hypertension, and evidence of cardiovascular pathology.

High Risk Blood Pressure and Obesity Increase the Risk for Left Ventricular Hypertrophy in African-american Adolescents

To examine the relative effects of high blood pressure (HBP) and obesity on left ventricular mass (LVM) among African-American adolescents; and if metabolic or inflammatory factors contribute to LVM.

The Adipose Tissue Production of Adiponectin is Increased in End-stage Renal Disease

Adiponectin has antidiabetic properties, and patients with obesity, diabetes, and insulin resistance have low plasma adiponectin levels. However, although kidney disease is associated with insulin resistance, adiponectin is elevated in end-stage renal disease. Here we determine whether adipose tissue production of adiponectin is increased in renal disease in a case-control study of 36 patients with end-stage renal disease and 23 kidney donors. Blood and tissue samples were obtained at kidney transplantation and donation. The mean plasma adiponectin level was significantly increased to 15.6 mg/ml in cases compared with 8.4 mg/ml in controls. Plasma levels of the inflammatory adipokines tumor necrosis factor α, interleukin 6, and high-sensitivity C-reactive protein were significantly higher in cases compared with controls. Adiponectin mRNA and protein expression in visceral and subcutaneous fat were significantly higher in cases than controls, while adiponectin receptor-1 mRNA expression was significantly increased in peripheral blood cells, muscle, and adipose tissue in cases compared with controls. Thus, our study suggests that adipose tissue production of adiponectin contributes to the high plasma levels seen in end-stage renal disease.Kidney International advance online publication, 2 January 2013; doi:10.1038/ki.2012.421.

A Genome-wide Methylation Study on Essential Hypertension in Young African American Males

There is emerging evidence from animal studies suggesting a key role for methylation in the pathogenesis of essential hypertension. However, to date, very few studies have investigated the role of methylation in the development of human hypertension, and none has taken a genome-wide approach. Based on the recent studies that highlight the involvement of inflammation in the development of hypertension, we hypothesize that changes in DNA methylation of leukocytes are involved in the pathogenesis of hypertension.

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