John Amerena

Vasoconstriction with norepinephrine causes less forearm insulin resistance than a reflex sympathetic vasoconstriction.

We used the insulin-perfused human forearm model to assess the effects of vasoconstriction induced with norepinephrine on the extraction of glucose in the forearm in two groups of healthy young volunteers. The norepinephrine findings were compared with a previously studied group in which vasoconstriction has been caused by reflex activation of the sympathetic nervous system. The aim of the study was to determine the relative importance of hemodynamic and receptor-mediated mechanisms of insulin resistance. Plasma insulin, arterial and venous glucose samples, and forearm blood flow were measured at 10-minute intervals during a 30-minute baseline, a 60-minute intra-arterial insulin infusion, and during 30 minutes of insulin infusion plus vasoconstriction. Group 1 (n = 14) had physiological vasoconstriction induced by inflation of bilateral thigh cuffs to 40 mm Hg to cause pooling of blood in the lower extremities and reflex vasoconstriction in the forearm; group 2 (n = 8) had intra-arterial infusion of norepinephrine to achieve the same degree of vasoconstriction as seen with inflation of thigh cuffs in group 1. Subjects in group 3 (n = 7) had infusion of intra-arterial norepinephrine to achieve a twofold increase in physiological vasoconstriction. With a physiological decrease in forearm blood flow (group 1), there was a 19% decrease in forearm blood flow resulting in a 23% reduction in glucose uptake in the forearm (P < .03). The same degree of reduction in forearm blood flow with a predominantly alpha-adrenergic agonist, norepinephrine (group 2), causes much less insulin resistance (a decrease in utilization of 13%) (P < .04).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin Mediates Forearm Glucose Uptake by Hemodynamic Rather Than Direct Effects

Insulin sensitivity may be improved with the angiotensin-converting enzyme inhibitor captopril, suggesting that inhibition of angiotensin II (Ang II) improves insulin resistance. However, the administration of systemic Ang II has also been associated with an improvement in rather than worsening of glucose utilization. Since both stimulating and antagonizing the renin-angiotensin system improve glucose uptake and both angiotensin-converting enzyme inhibitors and intravenous Ang II elicit skeletal muscle vasodilation, it is conceivable that hemodynamic factors rather than a direct effect of either Ang II or angiotensin-converting enzyme inhibitors on skeletal muscle metabolism modulate the increase in glucose utilization. The direct effects of Ang II on glucose extraction in intact human skeletal muscle have not been previously described. We investigated the effects of local infusion of Ang II on glucose uptake in the forearm of 20 healthy subjects. With the use of the isolated insulin-perfused forearm model, local plasma insulin values were raised to 100 mU/mL over fasting values and maintained there for a 90-minute infusion period. After the first 60 minutes of insulin alone, Ang II was infused into the brachial artery for the last 30 minutes. Intra-arterial Ang II infusion caused a 38% decrease in forearm blood flow (P <.05) and 59% increase in the arteriovenous glucose gradients (P <.05) to maintain a steady glucose utilization (a decrease of 4%, P=NS). Thus, local Ang II infusion does not impair insulin-stimulated glucose utilization. Furthermore, glucose extraction increases to compensate for the decrease in forearm blood flow (as the Fick principle would predict for freely diffusible substances). We conclude that the described increase in glucose utilization from systemic infusion of Ang II and during angiotensin-converting enzyme inhibitor treatment is mediated by hemodynamic factors rather than a direct effect of Ang II on skeletal muscle metabolism.

Hematocrit levels and physiologic factors in relationship to cardiovascular risk in tecumseh, michigan

Objective To investigate the relationship between hematocrit, blood pressure and other known cardiovascular risk factors. Design The Tecumseh Blood Pressure Study includes a cohort of subjects of average age 29.5 years (346 male, 277 female) who reside in Tecumseh, Michigan, USA Methods The body weight; home, work and clinic blood pressures; hematocrit level, plasma renin activity, baseline and mentally stimulated plasma catecholamines level; and fasting glucose, insulin and lipids levels were obtained. Since menstruation and childbearing affect the hematocrit, results are presented only for males. The males in Tecumseh were divided into tertiles of hematocrit (group I ≤43.25, group II 43.26–45.2 and group III >45.2%) Results Higher hematocrit levels were significantly related to higher blood pressures at home, at work and in the clinic, although all of the values measured were within the normotensive range (128/79 mmHg clinic blood pressure in group III). The metabolic factors weight, cholesterol, triglycerides, insulin and glucose levels were significantly elevated in group III. The weight affected only the relationship of hematocrit to plasma insulin levels and not the other variables including the blood pressure. Groups II and III showed signs of sympathetic overactivity; their plasma renin levels, heart rates and norepinephrine levels after mental stimulation were elevated Conclusions Although the relationship of blood pressure to the hematocrit level was previously known, in Tecumseh hematocrit is also found to be associated with several other cardiovascular risk factors and with signs of a hypersympathetic state. We intend to evaluate prospectively the relative prognostic significance of a higher hematocrit level versus the other associated risk factors

Impact of ethnicity on left ventricular mass and relative wall thickness in essential hypertension

This study was designed to evaluate the impact of ethnicity on left ventricular (LV) mass, and relative wall thickness in 527 patients (57% men, mean age 60 +/- 7 years) with mild to moderate high blood pressure. There were 63% Caucasians, 21% African-Americans, and 16% Hispanics. LV mass was indexed according to body surface area, height, and height to the allometric power of 2.7. Relative wall thickness included the 4 widely recognized patterns: normal, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. LV mass indexed to body surface area was similar among all 3 ethnic groups (Caucasians 117.1 g/m2, African-Americans 119.2 g/m2, Hispanics 122.7 g/m2); however, when indexed to height and height to the power of 2.7, Hispanics had slightly larger masses than the other 2 groups (Hispanics 168.1 and 73.3 g/m2.7 vs Caucasians 159.8 and 64.4 g/m2.7 [p = NS and p < 0.005]; and vs African-Americans 164.8 and 69.2 g/m2.7 [p = NS for both]). Using body surface area, the concentric remodeling was the predominant form of cardiac adaptation in Caucasians (36%) and African-Americans (42%), whereas the concentric hypertrophy pattern was 38% in Hispanics. Using indexing for both height and height to the power of 2.7, the concentric hypertrophy pattern predominated in all 3 ethnic groups (Caucasians 48% and 51%; African-Americans 68% and 66%; Hispanics 59% and 65%). In conclusion, because of the independent impact of weight on high blood pressure, LV mass adjusted to height or to height at the power of 2.7 should be reported in population studies. The concentric hypertrophy pattern--classic LV response to pressure overload conditions--is better represented when LV mass is indexed to height or to height to the allometric power of 2.7 than to body surface area.

Parental Hyperdynamic Circulation Predicts Insulin Resistance in Offspring The Tecumseh Offspring Study

Controversy surrounds the pathogenetic mechanisms of the relationship between hyperdynamic circulation and insulin resistance. Two hundred eight children and young adults (mean age, 17.2+/-3.0 years; range, 11 to 26 years) from the Tecumseh Offspring Study whose parents had been assessed with Doppler echocardiography at the age of 34 years during the previous Tecumseh Blood Pressure Study were considered for this analysis. Offspring data were stratified according to tertiles of parental cardiac index. Parents in the top cardiac index tertile had increased heart rate (P=0.001), stroke volume (P=0.0001), left ventricular fractional shortening (P=0.02), and plasma epinephrine (P=0.02) compared with parents in the other tertiles. Body mass index (BMI) and blood pressure were similar in all groups. Offspring of parents with a high cardiac index had greater BMI (P=0.001), skinfold thickness (P=0.008), and waist/hip ratio (P=0.02), higher diastolic blood pressure (P=0.02) and plasma insulin level (P=0.001), and higher heart rate during Stroops color test (P=0.02) than offspring of parents with a lower cardiac index. In a multivariate regression analysis, offspring BMI was predicted by parental BMI and cardiac index (P=0.0001 and 0.003, respectively). The mother-child relationship explained most of the cardiac index-BMI association. In summary, parental hyperdynamic circulation was an important predictor of overweight, abnormal fat distribution, increased blood pressure, and hyperinsulinemia in offspring. Our results illustrate the complexity of interaction between a genetic tendency and its phenotypic expression. We speculate that the degree of beta-adrenergic responsiveness may be a major determinant of the phenotypic differences between the parents and offspring found in this study.

A gender blind relationship of lean Body mass and blood pressure in the tecumseh study

BACKGROUND Body size correlates positively with blood pressure (BP) but there is controversy about the roles of obesity versus muscularity in this relationship. METHODS We examined the BP relationship with overweight, lean body mass (LBM), and muscle performance in 231 adolescents (17.25 +/- 3.07 years, 123 males). The skinfold thickness (SKINT) was used to measure overweight, as this was a growing population. RESULTS Maximal foot torque, a measure of muscle strength, correlated strongly (r = 0.51, P < .001) to LBM attesting to the validity of the calculated LBM. Anthropometric measurements were available also in 944 adults (29.9 +/- 5.5 years, 461 men). Correlations of LBM to systolic (adolescents r = 0.52, adults r = 0.19, both P < .001) and diastolic (adolescents r = 0.47, adults r = 0.20, both P < .001) BP were highly significant. SKINT also correlated significantly to systolic and diastolic BP in adolescents and in adults, respectively. In both genders and populations an increasing SKINT was associated with a similar increase in BP, but this effect was superimposed on an average 10 mm Hg between-gender BP difference. The LBM in both groups and genders related to the BP in an identical fashion; the men were on the high and the women on the low end of the same BP/LBM correlation line. Thus, the amount of LBM erased categoric BP differences between the genders. CONCLUSIONS The gender-related BP differences appear to reflect the inherent gender differences in muscle bulk.

Determinants of left ventricular structure and mass in young subjects with sympathetic over-activity. The Tecumseh Offspring Study.

Objective In this study, we tested the hypothesis that sympathetic over-activity may cause metabolic abnormalities and affect left ventricular (LV) structure and mass early in life. Subjects and setting The study population consisted of 111 healthy adolescents and young adults living in Tecumseh, Michigan (USA). Main outcome measures Correlations of LV mass and structure with several clinical variables in relation to the activity of the sympathetic nervous system. Methods Power spectrum density estimates of heart rate variability were calculated with an auto-regressive method, and subjects were divided by cluster analysis into two groups according to low-frequency and high-frequency components. LV data were obtained by echocardiographic assessment. Results Subjects with signs of sympathetic over-activity (n = 38, group 1) had higher heart rate, blood pressure (BP), waist/hip ratio and cholesterol levels than the rest of the group (n = 73, group 2). In group 1 subjects, insulin emerged as the strongest univariate correlate of interventricular septum and posterior wall thicknesses (P <0.001 for both) and of LV mass (P = 0.009). These relationships remained significant when body mass index was accounted for. By contrast, the marginal univariate relationship with diastolic BP did not remain significant in multivariate analysis. In group 2 subjects, BP was strongly correlated with LV wall thickness and mass both in univariate (P values from 0.03 to <0.001) and multivariate analyses, while insulin was not. The interactive effect of sympathetic activity and insulin on echocardiographic data was confirmed by multivariate analyses performed in the subjects grouped together (P values from 0.02 to 0.001 for the sympathetic activity × insulin interaction term). Conclusions In young subjects with heightened sympathetic activity and initial metabolic abnormalities, insulin is a strong determinant of LV wall thickness and geometry, while in subjects with normal autonomic nervous system activity, the main determinant of left ventricular size is the haemodynamic load.

Role of left ventricular hypertrophy in diastolic dysfunction in aged hypertensive patients.

Objective To evaluate the influence of left ventricular hypertrophy (LVH) on the diastolic dysfunction in older hypertensive patients. Methods In total 665 patients (58% men, 61% White, aged 55–80 years) with mild-to-moderate essential hypertension underwent Doppler echocardiography. Data included left ventricular dimensions, left ventricular mass index, body mass index, E- and A-wave mitral flow velocities, E:A ratio, deceleration time and three mitral flow patterns [normal (E:A ratio >1.0, deceleration time >150 ms), impaired relaxation (E:A ratio <1.0, prolonged deceleration time according to age), and restrictive physiology (E:A ratio >2.1, deceleration time <150 ms)]. Data were distributed according to age (50–59, 60–69, and 70–80 years). Results The overall prevalence of sex-adjusted LVH in this study was 65%. When we compared hypertensive patients with and without LVH, the E- and A-wave velocities, E:A ratio, and deceleration time were similar. Moreover, the prevalences of normal, impaired relaxation, and restrictive physiology patterns among patients with and without LVH did not differ significantly (20, 79.5, and 0.5 versus 24, 75.5, and 0.5%). When the mitral flow patterns were adjusted according to age, the impaired relaxation pattern increased further with age (to 73% during the fifth decade, 83% during the sixth decade, and 88% during the seventh decade). Conclusions LVH is not an independent factor associated with abnormal flow patterns in hypertensive patients aged over 50 years with normal systolic contractility. The impaired relaxation is the predominant pattern of diastolic dysfunction in older hypertensive patients and increases further with aging.

Genetic contribution to the variance in left ventricular mass: The Tecumseh offspring study

Objective To estimate the contribution of heredity to the variance in left ventricular mass (LVM), and to ascertain whether genetic factors may interact with non-genetic factors in promoting LVM growth. Subjects and setting The study population consisted of 290 healthy parents and 251 healthy children living in Tecumseh, Michigan, USA. Main outcome measure Correlation of parents’ LVM with offsprings LVM adjusting for a number of clinical variables. Methods LVM in parents and offspring was measured with M-mode echocardiography by the same investigators. Results Parents unadjusted LVM was unrelated to offspring unadjusted LVM , but after removing the confounding effect of age, sex, anthropometric measurements, systolic blood pressure, plasma insulin and urinary sodium excretion, parent–child correlation for LVM was 0.28 (P = 0.006). The relative contribution of parental-adjusted LVM and of several offspring phenotypic and environmental variables on offspring LVM was evaluated by multivariable regression analysis. When age, gender, anthropometric measurements and systolic blood pressure were accounted for, adjusted LVM of parents explained only 1.6% of the total variance in offspring LVM. However, after inclusion of insulin and urinary sodium in the model heredity explained 7.6% of the total variance in offspring LVM, and its predictive power was second only to that of childs height. Furthermore, an interactive effect of parental LVM with offspring systolic blood pressure was found on childs left ventricular mass. Conclusion Heredity can explain a small, but definite proportion of the variance in LVM. Higher blood pressure favors the phenotypic expression of the genes that regulate LVM growth.

Heritability of left atrial size in the Tecumseh population.

Background  Little is known about the determinants of atrial size, and no study has analyzed whether genetic factors are involved in the pathogenesis of LA enlargement.