Barry M. Stults

Apolipoprotein, low density lipoprotein subfraction, and insulin associations with familial combined hyperlipidemia. Study of Utah patients with familial dyslipidemic hypertension.

Familial dyslipidemic hypertension (FDH) Is a syndrome recently described from sibshlps selected for early familial hypertension and found to have one or more of three fasting llpld abnormalities [high trlglycerldes, low high density lipoprotein (HDL) cholesterol, high low density lipoprotein (LDL) cholesterol]. In further analyses of these same 131 hypertensive subjects, apolipoprotein A-l and B, fasting plasma Insulin (adjusted for body mass Index), and detailed anthropometries were different In two subgroups of FDH. Of 63 FDH patients, 19 met the criteria for familial combined hyperlipidemia (FCHL); 44 did not, but still had high triglycerlde and/or low HDL cholesterol levels. When compared to 20 normollptdemlc hypertensive patients, the 19 hypertensive patients with FCHL had 196% higher very low density lipoprotein cholesterol (p=0.0001), 33% higher apolipoprotein B (p=0.0002), smaller LDL particles (p=0.007), and 73% higher fasting Insulin (p=0.003), but no significant differences in body mass Index or sklnfold thicknesses. The other 44 FDH patients without FCHL had 33% lower HDL (p=0.0001), with only 8% lower apolipoprotein A-l levels (p=0.20); significantly higher subscapular sklnfolds (p=0.02), weights (p=0.002), body mass Index (p=0.006), knee widths (p=0.0007), and wrist circumferences (p=0.0009); smaller, denser LDL subtractions (p=0.001); and Increased apolipoprotein B levels (p=0.01) compared to the normolipldemlc hypertensive group. Increased fasting Insulin levels were similar to the normollpldemlc group and significantly lower than the FCHL group after adjustment for body mass index, suggesting a relationship between obesity and fasting Insulin levels only in the non-FCHL group. We conclude that FDH consists of at least two subgroups: 1) FCHL with high apolipoprotein B, small LDL particles, and Increased fasting plasma Insulin levels, and 2) a less well-defined residual having upper central obesity with low HDL cholesterol and high triglycerlde levels. Elevated insulin levels found In both groups, but possibly originating through different physiological mechanisms, may provide the pathophyslologlcal connections between dysllpldemia, obesity, and hypertension.

Family history as an independent risk factor for incident coronary artery disease in a high-risk cohort in Utah

To test independence of family history of coronary artery disease (CAD) as a risk factor for the development of new clinical CAD, data collected at 2 clinic visits on 1,196 men and women, ages greater than 20 years, were analyzed using Cox proportional hazard method. During a mean follow-up of 2.5 years, 16 new CAD cases were observed. After adjustment for age, sex, total cholesterol, high density lipoprotein cholesterol, hypertension, diabetes, cigarette smoking and body mass index, family history remained a highly significant predictor of future CAD (p = 0.0017). Only age was a more significant covariate (p = 0.0001) than family history. Sex (p = 0.00074) and serum total cholesterol (p = 0.015) also contributed significantly to CAD incidence while high density lipoprotein cholesterol, hypertension, diabetes, body mass index and several interaction terms did not improve the prediction in this population. These results provide evidence for the existence of other heritable risk factors which appear to contribute strongly to the occurrence of early CAD in many high-risk families.

Treatment of the elderly hypertensive patient

It is generally accepted that increased blood pressure, especially high systolic blood pressure, is a major risk indicator in people over 60 years of age. Retrospective analyses of published trials show that when the elevation in arterial pressure has been firmly established by repeated blood pressure measurements, antihypertensive treatment should be considered for the following subgroups (1) All elderly hypertensive patients with grade III or IV retinopathy, congestive heart failure or cerebral infarction or hemorrhage should be treated regardless of age or degree of blood pressure elevation (2) In elderly patients with established mild hypertension and no symptoms or complications, non-pharmacological treatment should be started in patients less than 80 years of age, with antihypertensive drugs prescribed if diastolic pressure reaches lOOmmHg or more over 3 months or 95mmHg or more over 6 months of follow-up. The therapeutic benefit of pharmacologic antihypertensive treatment has not yet been established in hypertensive patients over 80 years of age or in those with isolated systolic hypertension All things considered, the indication to intervene pharmacologically should be viewed as becoming gradually more compelling as blood pressure rises. The more closely a patients characteristics match those of a subset of elderly hypertensive patients in whom therapeutic benefit has been proven, the greater the need for pharmacologic treatment

Blood pressure reactivity in adult male twins.

The purpose of the present investigation was to examine possible genetic contributions to cardiovascular reactivity by contrasting patterns of association in 82 monozygotic (MZ) and 88 dizygotic (DZ) adult male twin pairs (age range = 21 to 61 years, M = 35 years). Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were recorded during baseline and during a mental arithmetic task (i.e., serial subtraction). The task produced significant elevations in all three cardiovascular measures (i.e., 10 mmHg SBP, 8 mmHg DBP, and 6 bpm HR, respectively). Levels of SBP and DBP reactivity were significantly correlated in MZ pairs but not in DZ pairs. Statistical tests suggest a heritability estimate of about 50% that was marginally significantly for SBP and DBP changes during the task. There was no indication of a genetic influence on HR reactivity. Resting level and static task period measures of SBP, DBP, and HR demonstrated statistically significant heritability estimates of 60% to 80%.

Definition of genetic factors in hypertension: A search for major genes, polygenes, and homogeneous subtypes

Summary: Essential hypertension is a heterogeneous group of disorders with different causes. This report report reviews approaches taken and results found in current studies of the genetic and environmental determinants of essential hypertension. Recent observations from the University of Utah Cardiovascular Genetics Research Clinic and published data from other studies are cited. Several biochemical tests show strong associations with hypertension and substantial major gene and or poly genie determination including: urinary kallikrein eeretion, intracellular sodium concentration. Sodium-lithium countertransport, plasma haptoglobin phenotypes. MN blood group, and famitial dyslipidemia.

Genetics of Hypertension: What We Know and Don't Know

Human arterial hypertension is likely a multifactorial trait resulting from multiple measurable monogenes, blended polygenes, shared family environment, and individual environment. Familial aggregation of hypertension and familial correlation of blood pressure appears to be more due to genes than to shared family environment. Total genetic heritability of 80% with some recessive major gene effects have been found for several traits associated with hypertension including urinary kallikrein excretion, intraerythrocytic sodium, and sodium-lithium countertransport. Other interesting factors regarding hypertension genetics include: non-modulation of the renin angiotensin system, intralymphocytic sodium, ionized calcium, and several genetic markers such as haptoglobin, HLA, and MNS blood type. Probably the most clinically useful information regarding the genetics of hypertension is evolving in several studies reporting a strong association of hypertension with dyslipidemia, diabetes, and obesity.

Platelet-derived growth factor — A growth factor with an expanding role in health and disease

Platelet-derived growth factor (PDGF) is the principal mitogen for connective tissue-derived cells such as fibroblasts, smooth muscle cells, and glial cells. It is synthesized by a variety of cell types and the synthesis of PDGF and its receptors is tightly controlled. Accumulating evidence obtained in vitro and in vivo suggests that PDGF plays important roles in the pathogenesis of clinically important diseases such as atherogenesis and cancer. Moreover, PDGF is an important research tool to study the signal transmission pathway of growth factors and other hormones.SummaryPlatelet-derived growth factor (PDGF) is the principal mitogen for connective tissue-derived cells such as fibroblasts, smooth muscle cells, and glial cells. It is synthesized by a variety of cell types and the synthesis of PDGF and its receptors is tightly controlled. Accumulating evidence obtained in vitro and in vivo suggests that PDGF plays important roles in the pathogenesis of clinically important diseases such as atherogenesis and cancer. Moreover, PDGF is an important research tool to study the signal transmission pathway of growth factors and other hormones.

Current knowledge regarding the genetics of human hypertension

Observations over 11 years from the University of Utah Cardiovascular Genetics Research Clinic and published data from other studies are reviewed to illustrate research approaches, developing results and prospects for future studies. Strong associations with hypertension have been found for several biochemical tests that show substantial genetic determination. Suggestions of recessive major gene effects and significant polygenic background determinations have been found for several variables, including urinary kallikrein excretion, intracellular sodium concentration, sodium-lithium countertransport and sodium-potassium cotransport. Each of these variables is related in some way to sodium or potassium metabolism, or both, and may help to improve the understanding of a possibly inherited susceptibility to hypertension that is related to dietary electrolyte intake. A second major group of factors involving familial predisposition to hypertension include lipid abnormalities (increased very-low- and low-density lipoprotein cholesterol and decreased high-density lipoprotein cholesterol); increased fasting insulin levels or insulin resistance, or both; obesity (especially central or upper body obesity); and multiple environmental factors influencing these metabolic systems, including dietary fat, carbohydrate and calorie intake; physical exercise; and certain antihypertensive medications that adversely affect lipid metabolism and glucose tolerance. Some studies even suggest a possible link between these two large groups of factors (electrolyte metabolism and lipid-insulin metabolism). Hypertriglyceridaemia and hyperinsulinaemia are both significantly correlated with increased levels of several cation-flux tests. It is recommended that studies of human hypertension apply these biochemical profiles to study sibships with two or more hypertensive siblings as a cost-effective initial approach.(ABSTRACT TRUNCATED AT 250 WORDS)

A digoxin-like factor associates with erythrocyte sodium concentration, sodium transport, and ouabain binding

To investigate what effects a circulating digoxin-like factor (DLF) might have on sodium metabolism, we examined data collected on 1,327 individuals screened in the Cardiovascular Genetics Clinic at the University of Utah. This sample included 639 unmedicated adults, 582 youths under age 18, and 106 medicated hypertensive individuals, all on an unrestricted diet when attending clinic. No individuals look digitalis. A digoxin assay detected measurable levels of plasma DLF in 13.4% of the youths, 17.2% of the normotensive adults, and 25.5% of the hypertensive adults. In all three groups of individuals, those with a measurable DLF had a significantly lower erythrocyte ouabain sensitive sodium efflux rate constant (adjusted for age, sex and body mass) than those with no measurable DLF (p less than 0.01). Normotensive and hypertensive adults with measurable DLF also had an increased erythrocyte intracellular sodium level. Either the number of ouabain binding sites and/or the apparent affinity for ouabain were reduced for those with DLF levels in all three groups. There was a small nonsignificant increase in blood pressure for the normotensive adults and youths with a measurable DLF. We conclude that plasma DLF is associated with reduced ouabain sensitive sodium transport and increased intracellular sodium concentration, possibly due to changes in the number of or the competition for the Na+ - K+ ATPase sites.

The Prevalence and Clinical Correlates of an Auscultatory Gap in Systemic Sclerosis Patients

Introduction. Accurate blood pressure (BP) measurement is essential to the diagnosis and management of hypertension in patients with systemic sclerosis (SSc) to help prevent renal and cardiovascular complications. The presence of an auscultatory gap during manual BP measurement—the temporary disappearance of the Korotkoff sounds during cuff deflation—leads to a potentially important underestimate of systolic BP if undetected. Objectives. Since the presence of an auscultatory gap is frequently associated with increased vascular stiffness, we investigated its presence and correlates in 50 consecutive SSc patients. Methods. For each patient, BP was measured sequentially using three different approaches performed in the same order. Results. Sixteen of 50 patients (32%) had an auscultatory gap which if undetected would have resulted in clinically important underestimates of systolic BP in 4 patients. The presence of an auscultatory gap was statistically associated with the presence of antibodies to RNA polymerase III (P<0.0068) and SSc diagnosis type (P<0.01). Conclusions. Our study demonstrates that auscultatory gaps are relatively common in SSc and correlate with markers for SSc vasculopathy. If undetected auscultatory gaps may result in clinically important underestimation of BP. Thus, electronic oscillometric BP may be preferred in SSc patients.