Genetic and sociocultural components of high blood pressure

The cardiovascular diseases exert widely differing contributions to the total burden of mortality and morbidity in extant human populations. To a large extent these differences are a reflection of the variable distribution of specific antecedent risk factors. For one such risk factor, blood pressure, there is considerable variability in its distribution between different ethnic groups, especially between traditional and nontraditional societies. Intensive epidemiological studies in Western societies, together with a number of cross-cultural comparisons, suggest that the major determinants of high blood pressure are likely to be a constellation of sociocultural factors, with genetic determination being limited to the interaction between genotype and environment. Studies of populations in sociocultural transition offer an unique opportunity to identify the relative influence of specific sociocultural factors on the rate of change of blood pressure. In addition, when the study of such populations is placed in a quasi-experimental context, genetic-environmental interactions may also be detected. This strategy is illustrated by a study of the changing blood pressure distribution in Tokelauan migrants. Such an approach requires the initial definition of a response variable which measures change in blood pressure as a consequence of migration. The response variable, which identifies the relative influence of concomitants such as weight, age, and obesity, can then be subjected to genetic analysis. In the Tokelau case, blood pressure response tends to be positive in migrants but negative in non-migrants. Further statistical analysis indicates that there is a small proportion of high responders in both populations and that these cluster in families in the migrant population. However, estimates of the transmission parameter suggest that sociocultural transmission, rather than Mendelian segregation, is responsible. To date there is little evidence that genetic-environmental interactions have had any impact on the development of hypertension in this migrant population.     

Salt-sensing mechanisms in blood pressure regulation and hypertension

High salt consumption contributes to the development of hypertension and is considered an independent risk factor for vascular remodeling, cardiac hypertrophy, and stroke incidence. In this review, we discuss the molecular origins of primary sensors involved in the phenomenon of salt sensitivity. Based on the analysis of literature data, we conclude that the kidneys and central nervous system (CNS) are two major sites for salt sensing via several distinct mechanisms: 1) [Cl(-)] sensing in renal tubular fluids, primarily by Na(+)-K(+)-Cl(-) cotransporter (NKCC) isoforms NKCC2B and NKCC2A, whose expression is mainly limited to macula densa cells; 2) [Na(+)] sensing in cerebrospinal fluid (CSF) by a novel isoform of Na(+) channels, Na(x), expressed in subfornical organs; 3) sensing of CSF osmolality by mechanosensitive, nonselective cation channels (transient receptor potential vanilloid type 1 channels), expressed in neuronal cells of supraoptic and paraventricular nuclei; and 4) osmolarity sensing by volume-regulated anion channels in glial cells of supraoptic and paraventricular nuclei. Such multiplicity of salt-sensing mechanisms likely explains the differential effects of Na(+) and Cl(-) loading on the long-term maintenance of elevated blood pressure that is documented in experimental models of salt-sensitive hypertension.     

Circadian blood pressure rhythm in primary and secondary hypertension.

Circadian blood pressure variability was recorded in patients with primary hypertension and with different forms of secondary hypertension using ambulatory 24-h blood pressure measurement. A group of 20 patients with different forms of secondary hypertension was compared with a matched group of patients with primary hypertension. Although the mean 24-h blood pressure was not different between the two groups, the patients with secondary hypertension had significantly higher systolic blood pressure during sleep and higher systolic and diastolic blood pressure in the early morning, compared with the primary hypertension group. This nocturnal blood pressure fall was then investigated in various groups of patients with different forms of secondary hypertension and compared with normotensives and patients with primary hypertension. Patients with mild primary hypertension (n = 152) and with severe primary hypertension (n = 30) had the same blood pressure fall (14-16 mm Hg systolic and diastolic) during the night (23:00-05:00 h) as normotensives (n = 20). However, in patients with renoparenchymal hypertension (n = 29), renovascular hypertensions (n = 20), hyperaldosteronism (n = 6), and hyperthyroidism (n = 14), the nocturnal blood pressure fall was significantly (p less than 0.01) reduced. One patient with coarctation of the aorta and nine patients with primary hyperparathyroidism and elevated blood pressure had a normal circadian blood pressure profile with a normal nocturnal blood pressure fall. The heart rate decrease during the night was equal in all patient groups. Ambulatory blood pressure measurement allows blood pressure recording under everyday conditions, including nighttime. In primary hypertension the blood pressure variability exhibits the same circadian variation as in normotension, showing a marked nocturnal fall.(ABSTRACT TRUNCATED AT 250 WORDS)     

高血压患者心电图左心室高电压和左心室肥厚与血压的关系

目的:探讨原发性高血压患者常规心电图检测左心室高电压和左心室肥厚与血压的关系.方法:回顾分析我科2009年1月～2009年12月门诊及住院就医的各期原发性高血压患者92例临床资料,并与同期76例健康体检者对比.结果:高血压组心电图对左心室肥厚的检出率为15.22%,明显高于对照组,有统计学差异(x2=19.07,P<0.01);高血压组心电图对左心室高电压的检出率为20.65%,明显高于对照组,有统计学差异(x2=4.23,P<0.05).高血压组左心室肥厚率随着病情的加重逐渐加重,各级之间相比差异有统计学意义(P<0.01).左心室高电压情况各级之间相比差异亦有统计学意义(P<0.01),但与病情无明显的相关性.结论:心电图监测左心室肥厚和左心室高电压,简便易行,高血压患者应定期复查心电图,发现异常,积极降压等治疗.     

Comparative accuracy of neural network models for diagnosing latent arterial hypertension on the basis of data on daily blood pressure monitoring

Daily blood pressure monitoring was performed in 34 apparently healthy subjects and 72 patients with arterial hypertension (AH). We compared the efficiency of diagnosis of latent AH using models based on artificial neural networks of different architecture.     

Fenofibrate lowers blood pressure in two genetic models of hypertension

Fenofibrate, a commonly used lipid lowering drug, induces the expression of the gene coding for cytochrome P450-4A, whose major product is 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE, a potassium channel antagonist, could increase or decrease blood pressure (BP). We studied the effects of four weeks of oral fenofibrate on BP, urine output (UVol), plasma renin activity (PRA), and urine protein excretion in young (4-5 weeks) stroke prone spontaneously hypertensive rats (SHRSP), older (25 weeks) SHRSP, Dahl salt sensitive rats (Dahl S) on a high salt diet, Dahl S rats on a normal salt diet, and normotensive Sprague-Dawley (SD) rats. Fenofibrate prevented the increase in BP in 4-5 week old SHRSP, reduced BP in 25 week old SHRSP, but had no effect on BP in normotensive SD rats. Similarly, fenofibrate prevented the increase in BP in Dahl S rats on a high salt diet, but had no effect in Dahl S rats on a low salt diet. Fenofibrate increased UVol (and reduced weight gain) in young SHRSP and tended to increase it in other groups. It also increased PRA 2 to 5-fold in all groups except older SHRSP. Young SHRSP receiving fenofibrate excreted significantly less urine protein than control rats. The drug reduced proteinuria in Dahl S rats on high salt diet, but had no significant effect on proteinuria in other groups. In summary, fenofibrate reduced blood pressure and weight gain, increased UVol and PRA, and reduced urine protein excretion in young SHRSP. Other groups of animals showed these changes to a variable, but directionally similar extent. These findings are consistent with a natriuretic effect of fenofibrate.     

The BpTRU automatic blood pressure monitor compared to 24 hour ambulatory blood pressure monitoring in the assessment of blood pressure in patients with hypertension

Background

Increasing evidence suggests that ABPM more closely predicts target organ damage than does clinic measurement. Future guidelines may suggest ABPM as routine in the diagnosis and monitoring of hypertension. This would create difficulties as this test is expensive and often difficult to obtain. The purpose of this study is to determine the degree to which the BpTRU automatic blood pressure monitor predicts results on 24 hour ambulatory blood pressure monitoring (ABPM).

Methods

A quantitative analysis comparing blood pressure measured by the BpTRU device with the mean daytime blood pressure on 24 hour ABPM. The study was conducted by the Centre for Studies in Primary Care, Queen's University, Kingston, Ontario, Canada on adult primary care patients who are enrolled in two randomized controlled trials on hypertension. The main outcomes were the mean of the blood pressures measured at the three most recent office visits, the initial measurement on the BpTRU-100, the mean of the five measurements on the BpTRU monitor, and the daytime average on 24 hour ABPM.

Results

The group mean of the three charted clinic measured blood pressures (150.8 (SD10.26) / 82.9 (SD 8.44)) was not statistically different from the group mean of the initial reading on BpTRU (150.0 (SD21.33) / 83.3 (SD12.00)). The group mean of the average of five BpTRU readings (140.0 (SD17.71) / 79.8 (SD 10.46)) was not statistically different from the 24 hour daytime mean on ABPM (141.5 (SD 13.25) / 79.7 (SD 7.79)). Within patients, BpTRU average correlated significantly better with daytime ambulatory pressure than did clinic averages (BpTRU r = 0.571, clinic r = 0.145). Based on assessment of sensitivity and specificity at different cut-points, it is suggested that the initial treatment target using the BpTRU be set at <135/85 mmHG, but achievement of target should be confirmed using 24 hour ABPM.

Conclusion

The BpTRU average better predicts ABPM than does the average of the blood pressures recorded on the patient chart from the three most recent visits. The BpTRU automatic clinic blood pressure monitor should be used as an adjunct to ABPM to effectively diagnose and monitor hypertension.     

Circadian variations of catecholamines and blood pressure in patients with pseudohypoparathyroidism and hypertension

The relationship between 24-h recumbent blood pressure levels and secretory patterns of catecholamines was investigated in 4 patients with pseudohypoparathyroidism (PsHP) and hypertension and in 9 patients with essential hypertension. A clear circadian rhythm of blood pressure and catecholamines was documented in both groups with lowest levels of blood pressures and catecholamines occurring during sleep. During the 24-h period of recumbency mean arterial blood pressure (MAP) was correlated (r = 0.63, p less than or equal to 0.01) with plasma norepinephrine (N) in the patients with essential hypertension, but this correlation was weaker in patients with PsHP (r = 0.38, p less than or equal to 0.05). MAP was more closely related to plasma epinephrine (E) (r = 0.62, p less than or equal to 0.01) than to plasma NE in patients with PsHP. Plasma NE and E levels were considerably lower in patients with PsHP than in patients with essential hypertension throughout the 24-h recumbent period. The sleep-related decline in blood pressure and NE was less than in patients with essential hypertension. These results suggest that while the sympathetic nervous system may have a role in hour-to-hour maintenance of blood pressure in patients with PsHP and hypertension, it does not appear to be responsible for the elevated arterial pressure in these patients. Factors other than those investigated, such as obesity, alterations in sodium homeostasis of refractoriness of the vascular smooth muscle to the vasodilatory effect of PTH may be involved in the pathogenesis of hypertension in PsHP.     

Genetic basis of cancer

Tumorigenesis is a heterogeneous process that occurs over a relatively long time span, progressing from a single cell through intermediate stages to give rise to a tumour that becomes more aggressive over time. Recent discoveries have begun to define the molecular events that underlie this progression in breast and colon cancer.     

Genetic basis of sitosterolemia

The molecular mechanisms regulating the amount of dietary cholesterol retained by the body, as well as the body's ability to exclude other dietary sterols selectively, are poorly understood. An average Western diet will contain approximately 250-500 mg of dietary cholesterol and approximately 200-400 mg of non-cholesterol sterols, of which plant sterols are the major constituents. Approximately 50-60% of dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. There thus exists a subtle mechanism that allows the body to distinguish between cholesterol and non-cholesterol sterols. In sitosterolemia, a rare autosomal recessive disorder, affected individuals hyperabsorb and retain not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. Consequently, patients with this disease have very high levels of plant sterols in the plasma, and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. The STSL locus has been mapped to human chromosome 2p21. Mutations in two tandem ABC genes, ABCG5 and ABCG8, encoding sterolin-1 and -2, respectively, are now known to be mutant in sitosterolemia. The identification of these genes should now lead to a better understanding of the molecular mechanism(s) governing the highly selective absorption and retention of cholesterol by the body. Indeed, it is the very existence of this disease that has given credence to the hypothesis that there is a molecular pathway that regulates dietary cholesterol absorption and sterol excretion by the body.     

Effect of nifedipine and propranolol on blood flow,venous compliance and blood pressure in essential hypertension

To determine the efficacy of nifedipine combined with propranolol in the treatment of hypertension, 23 patients with essential hypertension uncontrolled while they were receiving propranolol, 120 mg/d, entered a dose response trial of four 8-week periods while continuing propranolol therapy. Therapy during the four periods consisted respectively of a placebo, 30 mg/d of nifedipine, 30 or 60 mg/d of nifedipine, and 30 or 60 mg/d of nifedipine along with only 60 mg/d of propranolol. Studies of forearm blood flow and venous compliance were carried out in nine of the patients. Ten patients dropped out after the first period. The mean blood pressures while the patients were recumbent after the first, second and third periods were 163 ± 17/100 ± 6, 147 ± 13/89 ± 10 and 141 ± 19/84 ± 10 mm Hg respectively. There was no evidence of tolerance in the four patients who received 30 mg/d of nifedipine during the third period. There was a significant dose-diastolic pressure response (p < 0.0006) without a change in heart rate in the eight who received 60 mg/d of nifedipine during this period. After 16 weeks of therapy with nifedipine 11 patients had a diastolic pressure less than 90 mm Hg while recumbent. While mean blood pressure and heart rate for the group were not significantly increased at the end of the fourth period, in three of the patients the diastolic pressure while recumbent increased to over 90 mm Hg. This suggests that 120 mg/d of propranolol is the minimum dose required for concomitant therapy. Adverse symptoms were mild and transient. Forearm plethysmography showed that nifedipine induced arteriolar but not venous dilation and that propranolol attenuated the vasodilator effect of nifedipine. The author concludes that nifedipine was safe and effective in combination with propranolol in this group of patients with essential hypertension.     

Vitamin C lowers blood pressure and alters vascular responsiveness in salt-induced hypertension

The present study was undertaken to investigate the effect of vitamin C treatment on blood pressure and vascular reactivity in salt-induced hypertension. Male Sprague-Dawley rats were fed a normal rat diet, a high-sodium (8% NaCl) diet, a normal rat diet plus vitamin C treament (100 mg x kg(-1) x day(-1)), or a high-sodium diet plus vitamin C treatment for 6 weeks. Salt loading significantly increased blood pressure, which was attenuated by vitamin C treatment. Aortic rings from the different groups were suspended for isometric-tension recording. The contractile response to noradrenaline was significantly increased in the salt-loaded rats. Vitamin C reduced the sensitivity of aortic rings to noradrenaline in rats on normal and high-sodium diets. In noradrenaline-precontracted rings, the relaxation response to acetylcholine, which was attenuated in the salt-loaded rats, was restored by vitamin C treatment. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) abolished the enhanced response to acetylcholine caused by vitamin C. The results suggest that the antihypertensive effect of vitamin C is associated with a reduction in vascular sensitivity to noradrenaline and enhancement of endothelium-dependent relaxation due to increased nitric oxide bioavailability.     

Effect of stress management on blood pressure in mild primary hypertension.

OBJECTIVE--To establish whether stress management had a larger effect than a control treatment on resting blood pressure, ambulatory blood pressure, and left ventricular mass. DESIGN--A 12 week baseline period of habituation to measurement of blood pressure was followed by randomisation to either stress management or mild exercise for six months and follow up six months later. SETTING--General practice, district general hospital, and medical school. PATIENTS--Of the 184 patients aged under 60 with mild primary hypertension who entered the baseline habituation period, 88 were excluded because they failed to meet the entry criteria or they withdrew from the study. The remaining 46 men and 50 women underwent treatment. INTERVENTIONS--10 clinical sessions and daily practice at home of either stress management based on relaxation or non-aerobic stretching exercises. Mildly stressful 15 minute interviews before and after treatment. MAIN OUTCOME MEASURES--Diastolic and systolic blood pressure in the clinic and during 12 hours of ambulatory recording, and left ventricular mass measured by echocardiography. RESULTS--The patients'' blood pressure fell during habituation (systolic pressure from 152 mmHg to 140 mmHg, diastolic pressure from 98 to 93 mm Hg), but neither resting nor ambulatory blood pressure was changed by the treatments. Left ventricular mass was also unchanged. Blood pressure rose during the stressful interview, but this rise was reduced by stress management (systolic pressure rose by 7.4 mmHg before treatment and by 3.7 mmHg after treatment). CONCLUSION--Stress management of a type advocated for treating mild primary hypertension is ineffective in lowering blood pressure in patients who are well habituated to measuring blood pressure.