Gary K. Barlow

A comparison of positive family history definitions for defining risk of future disease

The relative risk of developing future coronary heart disease (CHD) or hypertension between positive and negative family history families is compared for different definitions of a positive family history when applied to life-table data for 94,292 persons. Having two or more first degree relatives with CHD identifies 8% of the population with relative risks of 3.3-5.9 for CHD before age 50. A quantitative family history score (FHS) compares the familys age and sex specific disease incidence to that expected in the general population and predicts future disease incidence in unaffected family members slightly better (relative risks = 3.4-6.9 for CHD before age 50). Using only one affected relative, even if affected at an early age (less than 55 years old) does not discriminate low and high risk families as well (relative risks = 1.4-3.9 for CHD before age 50). Similar results were obtained for family history of hypertension. There is an increase in future disease incidence for all ages with increasing FHS values (p less than 0.0001), which can be used as a continuous or categorical variable in analysis where family history is associated with a particular variable under study. These results provide a rational basis for choosing and applying specific definitions of a positive family history of coronary disease or hypertension in clinical, epidemiologic and genetic studies.

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%.

Documented need for more effective diagnosis and treatment of familial hypercholesterolemia according to data from 502 heterozygotes in Utah

A project to help Utah residents with heterozygous familial hypercholesterolemia (FH) identified affected individuals by collecting detailed questionnaires from: (1) very high-risk persons in computer files of screening data (very high cholesterol levels, very early coronary artery disease, and strong positive family history); (2) confirmed FH index cases from a university lipid clinic; and (3) relatives of any confirmed FH cases. Questionnaires were received from 2,143 persons identifying 101 living index cases and 502 relatives meeting the criteria for the diagnosis of FH. Finding new FH heterozygotes was about one fourth as expensive by tracing relatives of confirmed FH cases by evaluating very high-risk persons. Of those meeting criteria for the diagnosis of heterozygous FH, only 31% reported being told by their physicians that they had FH, only 42% indicated that they were taking a cholesterol-lowering prescription medication, and only 23% had reasonably controlled cholesterol levels (below the 90th percentile). However, the data also suggest that good control is achievable in motivated patients. Among 106 FH heterozygotes who were early responders to a second follow-up questionnaire, 79% were taking prescription medications, of whom 49% had achieved cholesterol levels below the 90th percentile, and 17% even achieved cholesterol levels below the 50th percentile. We conclude that most patients with heterozygous FH are not diagnosed and not adequately treated. We demonstrated how many of these persons needing help could be identified efficiently by tracing relatives of known index cases.

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.

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)