Homocysteine, a thrombogenic agent, suppresses anticoagulant heparan sulfate expression in cultured porcine aortic endothelial cells.

Previous studies showed that homocysteine, a thrombo-atherogenic and atherogenic agent, inhibits an endothelial thrombomodulin-protein C anticoagulant pathway. We examined whether homocysteine might affect another endothelial anticoagulant mechanism; i.e., heparin-like glycosaminoglycan-antithrombin III interactions. Incubations of porcine aortic endothelial cell cultures with homocysteine reduced the amount of antithrombin III bound to the cell surface in a dose- and time-dependent fashion. The inhibitory effect was observed at a homocysteine concentration as low as 0.1 mM, and the maximal suppression occurred at 1 mM of homocysteine after 24 h. In contrast with a marked reduction in the maximal antithrombin III binding capacity (approximately 30% of control), the radioactivity of [35S]sulfate incorporated into heparan sulfate on the cell surface was minimally (< 15%) reduced. The cells remained viable after homocysteine treatment. Although neither net negative charge nor proportion in total glycosaminoglycans of cell surface heparan sulfate was altered by homocysteine treatment, a substantial reduction in antithrombin III binding capacity of heparan sulfate isolated from homocysteine-treated endothelial cells was found using both affinity chromatography and dot blot assay techniques. The antithrombin III binding activity of endothelial cells decreased after preincubation with 1 mM homocysteine, cysteine, or 2-mercaptoethanol; no reduction in binding activity was observed after preincubation with the same concentration of methionine, alanine, or valine. This sulfhydryl effect may be caused by generation of hydrogen peroxide, as incubation of catalase, but not superoxide dismutase, with homocysteine-treated endothelial cells prevented this reduction, whereas copper augmented the inhibitory effects of the metabolite. Thus, our data suggest that the inhibited expression of anticoagulant heparan sulfate may contribute to the thrombogenic property resulting from the homocysteine-induced endothelial cell perturbation, mediated by generation of hydrogen peroxide through alteration of the redox potential.

Insertion/deletion polymorphism in the angiotensin-converting enzyme gene affects heart weight.

BACKGROUND: Angiotensin (Ang) II, a major regulatory factor for left ventricular mass, is generated from Ang I by ACE. ACE levels are associated with an insertion/deletion (I/D) polymorphism in the ACE gene. The ACE polymorphism should result in varied Ang II concentrations and hence affect left ventricular mass. We therefore investigated whether ACE genotype is a predictor of heart weight. METHODS AND RESULTS: From 693 consecutive patients autopsied between 1994 and 1998 in our hospital, patients with valvular disease, myocardial infarction, or cardiomyopathy were excluded. The remaining 443 autopsy patients were the subjects of our study. The heart weight at autopsy was corrected for body surface area. Genomic DNA was purified from the kidney, and ACE genotype was determined by polymerase chain reaction. Heart weight in the DD genotype (249. 9+/-49.9 g/m(2)) was significantly higher than that in the ID (230. 0+/-51.2 g/m(2); P<0.05) and II (226.8+/-49.8 g/m(2); P<0.01) genotypes. Heart weight was also positively related to age (r=0.145, P<0.0001) and coronary stenosis index (r=0.147, P=0.0019). Multiple regression analysis showed that a history of hypertension (P<0.0001), age (P=0.0001), and DD genotype (P=0.0154) were independent predictors of heart weight. CONCLUSIONS: ACE genotype predicts cardiac mass; however, it was less effective than epigenetic factors such as hypertension or age.

Association between arterial stiffness and platelet activation.

Increased arterial stiffness is strongly associated with atherosclerosis, while platelet activation is an important trigger of thrombotic events in patients with atherosclerosis. However, little is known about the effect of arterial stiffness on platelet activation. We therefore investigated the association between arterial stiffness and platelet activation in 38 normal volunteers (20 men and 18 women) aged 23-77 years (mean = 49 +/- 15 years). Arterial stiffness was assessed by measuring brachial-ankle pulse wave velocity (ba-PWV) and heart-brachial PWV (hb-PWV). Flow cytometric analyses were performed to evaluate platelet activation by measuring surface expression of P-selectin and platelet-neutrophil complexes (PNC) before and after activation by ADP. We also calculated the difference between basal and stimulated states of P-selectin and PNC to assess platelet activation reserve. PWVs were significantly correlated with age and BP (r = 0.60-0.81). For platelet activation and activation reserve, correlations with age were less strong but remained significant (r = 0.36-0.61), with the exception of P-selectin (not significant, NS), and correlations with SBP were similar (r = 0.35-0.53). A significant correlation was found between PWVs and platelet activation (r = 0.43-0.74). Multiple regression analysis demonstrated significant correlations between platelet activation and reserve and PWVs (coefficient = 2.17-6.59), when both age and BP were adjusted for simultaneously. In conclusion, platelet activation was associated with arterial stiffness, suggesting that arterial stiffness may play an important role in thrombotic events.

Depressive mood is independently related to stroke and cardiovascular events in a community.

By means of a multivariate Cox model, we investigated the predictive value of a depressive mood on vascular disease risk in middle-aged community-dwelling people. In 224 people (88 men and 136 women; mean age: 56.8 +/- 11.2 years) of U town, Hokkaido (latitude: 43.45 degrees N, longitude: 141.85 degrees E), a chronoecological health watch was started in April 2001. Consultations were repeated every 3 months. Results at the November 30, 2004 follow-up are presented herein. 7-day/24-h blood pressure (BP) and heart rate (HR) monitoring started on a Thursday, with readings taken at 30-min intervals between 07:00 h and 22:00 h and at 60-min intervals between 22:00 h and 07:00 h. Data stored in the memory of the monitor (TM-2430-15, A and D company, Japan) were retrieved and analyzed on a personal computer with a commercial software for this device. Subjects were asked to answer a self-administered questionnaire inquiring about 15 items of a depression scale, at the start of study and again after 1-2 years. Subjects with a score higher by at least two points at the second versus first screening were classified as having a depressive mood. The other subjects served as the control group. The mean follow-up time was 1064 days, during which four subjects suffered an adverse vascular outcome (myocardial infarction: one man and one woman; stroke: two men). Among the variables used in the Cox proportional hazard models, a depressive mood, assessed by the Geriatric Depression Scale (GDS), as well as the MESOR of diastolic (D) BP (DBP-MESOR) and the circadian amplitude of systolic (S) BP (SBP-Amplitude) showed a statistically significant association with the occurrence of adverse vascular outcomes. The GDS score during the second but not during the first session was statistically significantly associated with the adverse vascular outcome. In univariate analyses, the relative risk (RR) of developing outcomes was predicted by a three-point increase in the GDS scale (RR = 3.088, 95% CI: 1.375-6.935, P = 0.0063). Increases of 5 mmHg in DBP-MESOR and of 3 mmHg in SBP-Amplitude were associated with RRs of 2.143 (95% CI: 1.232-3.727, P = 0.0070) and 0.700 (95% CI: 0.495-0.989, P = 0.0430), respectively. In multivariate analyses, when both the second GDS score and the DBP-MESOR were used as continuous variables in the same model, GDS remained statistically significantly associated with the occurrence of cardiovascular death. After adjustment for DBP-MESOR, a three-point increase in GDS score was associated with a RR of 2.172 (95% CI: 1.123-4.200). Monday endpoints of the 7-day profile showed a statistically significant association with adverse vascular outcomes. A 5 mmHg increase in DBP on Monday was associated with a RR of 1.576 (95% CI: 1.011-2.457, P = 0.0446). The main result of the present study is that in middle-aged community-dwelling people, a depressive mood predicted the occurrence of vascular diseases beyond the prediction provided by age, gender, ABP, lifestyle and environmental conditions, as assessed by means of a multivariate Cox model. A depressive mood, especially enhanced for 1-2 years, was associated with adverse vascular outcomes. Results herein suggest the clinical importance of repetitive assessments of a depressive mood and the need to take sufficient care of depressed subjects. Another result herein is that circadian and circaseptan characteristics of BP variability measured 7-day/24-h predicted the occurrence of vascular disease beyond the prediction provided by age, gender, depressive mood and lifestyle, as assessed by means of a multivariate Cox model. Earlier, we showed that the morning surge in BP on Mondays was statistically significantly higher compared with other weekdays. Although a direct association between the Monday surge in BP and cardiovascular events could not be demonstrated herein, it is possible that the BP surge on Monday mornings may also trigger cardiovascular events. We have shown that depressive people exhibit a more prominent circaseptan variation in SBP, DBP and the double product (DP) compared to non-depressed subjects. In view of the strong relation between depression and adverse cardiac events, studies should be done to ascertain that depression is properly diagnosed and treated. Chronodiagnosis and chronotherapy can reduce an elevated blood pressure and improve the altered variability in BP and HR, thus reducing the incidence of adverse cardiac events. This recommendation stands at the basis of chronomics, focusing on prehabilitation in preference to rehabilitation, as a public service offered in several Japanese towns.

Arterial stiffness independently predicts cardiovascular events in an elderly community -- Longitudinal Investigation for the Longevity and Aging in Hokkaido County (LILAC) study.

We investigated the predictive value of arterial stiffness to assess cardiovascular risk in elderly community-dwelling people by means of a multivariate Cox model. In 298 people older than 75 years (120 men and 178 women, average age: 79.6 years), brachial-ankle pulse wave velocity (baPWV) was measured between the right arm and ankle in a supine position. The LILAC study started on July 25, 2000, consultation was repeated yearly, and the last follow-up ended on November 30, 2004. During this follow-up span of 1227 days, there were nine cardiovascular deaths, the cause of death being myocardial infarction for two men and three women or stroke for two men and two women. In Cox proportional hazard models, baPWV as well as age, Mini-Mental State Examination (MMSE), Hasegawa Dementia Scale Revised (HDSR) and the low-frequency/high-frequency (LF/HF) ratio showed a statistically significant association with the occurrence of cardiovascular death. A two-point increase in MMSE and HDSR score significantly protected against cardiovascular death, the relative risk (RR) being 0.776 (P = 0.0369) and 0.753 (P = 0.0029), respectively. The LF/HF ratio also was significant (P = 0.025), but the other indices of HRV were not. After adjustment for age and HDSR, a 200 cm/s increase in baPWV was associated with a 30.2% increase in risk (RR = 1.302, 95% CI: 1.110-1.525), and a 500 cm/s increase in baPWV with a 93.3% increase in risk (RR = 1.933, 95% CI: 1.300-2.874, P = 0.0011), whereas the LF/HF ratio was no longer associated with a statistically significant increase in cardiovascular mortality. In elderly community-dwelling people, arterial stiffness measured by means of baPWV predicted the occurrence of cardiovascular death beyond the prediction provided by age, gender, blood pressure and cognitive functions. baPWV should be added to the cardiovascular assessment in various clinical settings, including field medical surveys and preventive screening. The early detection of risk by chronomics allows the timely institution of prophylactic measures, thereby shifting the focus from rehabilitation to prehabilitation medicine, as a public service to several Japanese towns.

Fractal analysis of heart rate variability and mortality in elderly community-dwelling people -- Longitudinal Investigation for the Longevity and Aging in Hokkaido County (LILAC) study.

AIM: Fractal analysis of heart rate (HR) variability (HRV) has been used as a new approach to evaluate the risk of mortality in various patient groups. Aim of this study is to examine the prognostic power of detrended fluctuation analysis (DFA) and traditional time- and frequency-domain analyses of HR dynamics as predictors of mortality among elderly people in a community. METHODS: We examined 298 people older than 75 years (average age: 79.6 years) and 1-h ambulatory ECG was monitored. During the last 10 min, deep respiration (6-s expiration and 4-s inspiration) was repeated six times in a supine position. Time-domain and frequency-domain measures were determined by the maximum entropy method. Scaling exponents of short-term (<11 beats, alpha 1) and longer-term (>11 beats, alpha 2) were determined by the DFA method. Six estimates, obtained from 10-min segments, were averaged to derive mean values for the entire recording span. These average values were denoted Alpha 1 and Alpha 2, estimates obtained during the first 10-min segment Alpha 1 S and Alpha 2 S, and those during the last 10-min segment Alpha 1E and Alpha 2E, respectively. The LILAC study started on July 25, 2000 and ended on November 30, 2004. We used Cox regression analysis to calculate relative risk (RR) and 95% confidence interval (CI) for all-cause mortality. Significance was considered at a value of P < 0.05. RESULTS: Gender, age and Alpha 2E showed a statistically significant association with all-cause mortality. In univariate analyses, gender was significantly associated with all-cause mortality, being associated with a RR of 3.59 (P = 0.00136). Age also significantly predicted all-cause mortality and a 5-year increase in age was associated with a RR of 1.49 (P = 0.01809). The RR of developing all-cause mortality predicted by a 0.2-unit increase in Alpha 2E was 0.58 (P = 0.00390). Other indices of fractal analysis of HRV did not have predictive value. In multivariate analyses, when both Alpha 2E and gender were used as continuous variables in the same model, Alpha 2E remained significantly associated with the occurrence of all-cause mortality (P = 0.02999). After adjustment for both gender and age, a 0.2-unit increase in Alpha 2E was associated with a RR of 0.61 (95% CI: 0.42-0.90, p = 0.01151). CONCLUSION: An intermediate-term fractal-like scaling exponent of RR intervals was a better predictor of death than the traditional measures of HR variability in elderly community-dwelling people. It is noteworthy that the longer-term (alpha 2) rather than the short-term fractal component (alpha 1) showed predictive value for all-cause mortality, which suggests that an increase in the randomness of intermediate-term HR behavior may be a specific marker of neurohumoral and sympathetic activation and therefore may also be associated with an increased risk of mortality.

Common carotid intima-media thickness is predictive of all-cause and cardiovascular mortality in elderly community-dwelling people: Longitudinal Investigation for the Longevity and Aging in Hokkaido County (LILAC) study.

Several cohort studies have examined the association of carotid intima-media thickness (IMT) with the risk of stroke or myocardial infarction in apparently healthy persons. We investigated the predictive value of IMT of cardiovascular mortality in elderly community-dwelling people, beyond the prediction provided by age and MMSE, assessed by means of a multivariate Cox model. Carotid IMT and plaque were evaluated bilaterally with ultrasonography in 298 people older than 75 years (120 men and 178 women, average age: 79.6 years). The LILAC study started on July 25, 2000. Consultations were repeated every year. The follow-up ended on November 30, 2004. During the mean follow-up span of 1152 days, 30 subjects (21 men and nine women) died. Nine deaths were attributable to cardiovascular causes (myocardial infarction: two men and three women; stroke: two men and two women). The age- and MMSE-adjusted relative risk (RR) and 95% confidence interval (95% CI) of developing all-cause mortality was assessed. A 0.3 mm increase in left IMT was associated with a RR of predicted 1.647 (1.075-2.524), and a similar increase in right IMT with a RR of 3.327 (1.429-7.746). For cardiovascular mortality, the corresponding RR values were 2.351 (1.029-5.372) and 2.890 (1.059-7.891), respectively. Carotid IMT assessed by ultrasonography is positively associated with an increased risk of all-cause and cardiovascular death in elderly community-dwelling people.

Measurement of plasma brain natriuretic peptide level as a guide for cardiac overload.

OBJECTIVES: We examined whether measurement of the plasma BNP concentrations might be useful for the early diagnosis of the existence and severity of disease in patients with heart disease in daily clinical practice. METHODS AND RESULTS: The plasma BNP and ANP concentrations in 415 patients with heart disease and hypertension and 65 control subjects were measured. Patients with heart disease had higher plasma BNP and ANP concentrations than did those with hypertension or control subjects. Among the etiology of cardiac diseases, specifically dilated cardiomyopathy and hypertrophic cardiomyopathy, was associated with the highest plasma BNP concentrations, whereas dilated cardiomyopathy was associated with the highest plasma ANP concentrations. Plasma BNP concentrations showed an increase as the severity of the heart disease, as graded according to the NYHA classification of cardiac function, increased. In both patients with heart disease and hypertension, the plasma BNP values were higher in those who had abnormalities in their echocardiogram and electrocardiogram as compared to those without any abnormalities. The plasma BNP levels also showed a significant correlation with left ventricular wall thickness and left ventricular mass. On the other hand, the plasma ANP levels showed significant correlations with left ventricular dimension. Receiver operative characteristic analysis revealed that plasma BNP levels showed substantially high sensitivity and specificity to detect the existence of heart diseases. CONCLUSION: Measurements of the plasma BNP concentrations is useful to detect the existence of the diseases, and abnormalities of left ventricular function and hypertrophy in patients with heart disease in daily clinical practice.

Accuracy of a continuous blood pressure monitor based on arterial tonometry.

A validation study of the continuous noninvasive tonometric blood pressure monitor called JENTOW was performed in 20 normotensive subjects and 10 hypertensive patients. Tonometric and intra-arterial blood pressures were simultaneously recorded at supine rest and during a Valsalva maneuver and tilting test. The results of the strict evaluation of the instrument's capacity for reproducing intra-arterial blood pressure were as follows: 1) The overall frequency response of the transcutaneous blood pressure-monitoring system based on arterial tonometry was flat, with negligible delay to intra-arterial blood pressure in the range of 0-5 Hz. 2) The largest discrepancy between intra-arterial and tonometric pressure waveforms was found at the early systolic phase; except for this phase, the tonometric waveform was almost equal to the intra-arterial waveform. 3) The beat-to-beat variability of tonometric pressure corresponded to that of intra-arterial pressure almost perfectly in the physiologically significant frequency range of 0-0.5 Hz. 4) During resting conditions, the averages of the systolic and diastolic values measured tonometrically corresponded well to those measured intra-arterially. 5) The changes in the between-method discrepancy of blood pressure values during the Valsalva maneuver were statistically significant but small (< 5 mm Hg). 6) No significant effect of postural tilting was found on the between-method discrepancy. We conclude that this method is clinically acceptable and reliable except for its limited capacity for recording the higher frequency intra-arterial waveform and for responding to the relatively rapid and large transient changes in blood pressure.

Endothelial-derived nitric oxide preserves anticoagulant heparan sulfate expression in cultured porcine aortic endothelial cells.

Nitric oxide (NO) has been shown to inhibit platelet adhesion and aggregation, but there are no reports on its interaction with the coagulation system. We investigated the effect of the L-arginine analogues, N-nitro-L-arginine (LNA), N(G)-nitro-L-arginine methyl ester (L-NAME), and N(G)-monomethyl-L arginine (L-NMMA), competitive inhibitors of NO production, on endothelial-surface heparan sulfate. Addition of LNA to porcine aortic endothelial cells reduced 125I-labeled antithrombin III binding to the cell surface heparan sulfate in a dose- and time-dependent fashion. Significant inhibition was observed with 1 mM LNA, and the maximal suppression (-50% of control) occurred at 10 mM LNA after 12 h. L-NAME (1 mM) and L-NMMA (1 mM) also significantly inhibited the antithrombin III binding. The iron chelator desferrioxamine significantly prevented the reduction of antithrombin III binding to LNA-treated cells. We further investigated the effect of L-NAME on intracellular oxidative stress of endothelial cells using a hydroperoxide-sensitive fluorochrome, carboxy-dichloro-dihydrofluorescein diacetate bisacetoxymethyl ester probe, and revealed that inhibition of NO synthesis by L-NAME led to a marked increase in intracellular oxidative stress. These results demonstrated that the prolonged inhibition of NO synthesis in porcine aortic endothelial cells decreases the expression of anticoagulant heparan sulfate on endothelial cells through the increase in intracellular oxidative stress, perhaps comprising another mechanism by which NO affects the coagulation system in the vasculature.

Alterations in cytosolic calcium-binding proteins that increase felodipine fluorescence in spontaneously hypertensive rats.

OBJECTIVE: To clarify the role of calcium-binding proteins (CaBP) in hypertension. DESIGN: CaBP from several organs of spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) rats were purified and their characteristics compared between the two strains. The CaBP were purified by applying the soluble cytosolic fractions from mesenteric vessels, heart, kidney and brain of 4- and 10-week-old SHR and WKY rats to a phenyl-Sepharose column. Felodipine binding to the purified CaBP was then measured. RESULTS: The fluorescence intensity of felodipine increased in a calcium-dependent manner when it bound to CaBP. The pK 0.5 Ca2+ values derived from the calcium ion-felodipine fluorescence curves for each CaBP preparation from organs of the two strains were similar, indicating that the calcium sensitivities of the CaBP to the felodipine binding process are similar in SHR and WKY rats. In 10-week-old SHR the mean levels of felodipine-bound CaBP in heart, brain and kidney were significantly altered compared with those in WKY rats. No such alterations were observed in heart, kidney and brain from 4-week-old SHR and WKY rats. Conversely, the mean levels of felodipine-bound CaBP in mesenteric vessels from 4- and 10-week-old SHR were reduced significantly compared with those of age-matched WKY rats. CONCLUSIONS: These results suggest that the levels of cytosolic felodipine-bound CaBP from heart, kidney and brain are altered in response to elevated blood pressure, and that reduced levels of felodipine-bound CaBP in the mesenteric vessels of SHR might be a primary characteristic of this rat strain.

Diurnal blood pressure variations and silent cerebrovascular damage in elderly patients with hypertension.

OBJECTIVE: To examine the effect of diurnal blood pressure changes upon cerebrovascular damage in elderly patients with hypertension. DESIGN: Fifty-four asymptomatic hypertensive and 34 normotensive elderly subjects underwent both 24-h non-invasive ambulatory blood pressure monitoring and brain magnetic resonance imaging. METHODS. Diurnal variation was defined as a difference of greater than or equal to 10 mmHg between mean awake and asleep systolic blood pressure. Hypertensives were thus classified as dippers or non-dippers. Low intense foci (lacunae) and advanced periventricular hyperintensity were identified as silent cerebrovascular damage. RESULTS: In the hypertensive group, lacunae were correlated more closely with mean asleep systolic blood pressure than with mean awake systolic blood pressure. Age, awake blood pressure, predicted whole blood viscosity, lipid profiles or quantity of sleep did not differ between the hypertensive dippers or non-dippers. The non-dippers, however, showed significantly higher grades of cerebrovascular damage as well as cardiac hypertrophy by electrocardiography than the dippers, whose results were similar to those of normotensives in this regard. CONCLUSIONS: An absent or lower nocturnal blood pressure fall in elderly hypertensives is associated with silent cerebrovascular damage. In contrast, the presence of a nocturnal fall could prevent the development of hypertensive vascular damage.

Altered levels of erythrocyte calcium-binding proteins in essential hypertensives with genetic predisposition: correlation with ambulatory blood pressure.

OBJECTIVE: To examine whether changes in calcium-binding proteins, one of the components of the calcium ion handling mechanism, occur in humans with essential hypertension. DESIGN: We measured the levels of cytosolic calcium-binding proteins purified from human erythrocytes using a felodipine fluorescence assay, and examined the correlation between this parameter and the ambulatory blood pressure (ABP). We divided 127 subjects into four age-matched groups according to their mean ABP levels and whether they had a family history of both hypertension and stroke [group A hypertensives with a positive family history (n = 30), group B hypertensives with no family history (n = 31), group C normotensives with a family history (n = 31) and group D normotensives with no family history (n = 35) of hypertension and stroke]. RESULTS: The erythrocyte cytosolic level of calcium-binding proteins in group A was significantly lower than that in group B, as was that in group C compared with group D. There was no significant correlation between the erythrocyte level of calcium-binding proteins and casual blood pressure values in any group. However, in group A significant negative correlations between the erythrocyte level of calcium-binding proteins and systolic and mean ABP were observed (r = -0.34, P < 0.05 and r = -0.39, P < 0.05, respectively). No significant correlations between the ABP and erythrocyte levels of calcium-binding proteins were observed in the other groups. When each group was subdivided according to sex, there were significant negative correlations between the erythrocyte level of calcium-binding proteins and the systolic and mean ABP in the males of groups A and C, but no correlations were found in any of the female subgroups or the males of groups B and D. Reducing the blood pressure by antihypertensive drug therapy did not affect the erythrocyte calcium-binding proteins level in 13 patients from groups A and B. Analysis using anion-exchange fast-performance liquid chromatography on a Mono-Q column and sodium dodecyl sulphate-polyacrylamide gel electrophoresis revealed that the calcium-binding proteins in human erythrocytes, the levels of which were low in group A, formed a single protein band with a molecular weight of 17,000, which was assumed to be a calmodulin. CONCLUSIONS: These results suggest that there are subgroups of hypertensive patients with low erythrocyte cytosolic levels of calcium-binding proteins, which are genetically determined. Furthermore, our data suggest that the erythrocyte level of calcium-binding proteins and ABP in male subjects with hypertension and normotensives with a genetic predisposition are correlated strongly, whereas no such correlation was observed in any female subgroup. This indicates that the regulatory mechanism or mechanisms involved in the control of blood pressure in men and women may be different.

Correlation between lipoprotein(a) and aortic valve sclerosis assessed by echocardiography (the JMS Cardiac Echo and Cohort Study).

An elevated serum level of lipoprotein(a) (Lp[a]) may be an independent risk factor for atherosclerotic disease, but the relation of Lp(a) to aortic valve (AV) sclerosis has not been determined. We measured serum concentrations of Lp(a) and investigated their relation to the presence of echocardiographic AV sclerosis in residents of a rural village in Japan. We measured serum Lp(a) levels in 347 men and 437 women aged 35 to 90 years (mean +/- SD: 62 +/- 11 years) who participated in mass screening examinations in Wara village, Gifu, Japan. AV sclerosis was assessed by long- and short-axis 2-dimensional echocardiographic views and continuous-wave Doppler echocardiography. AV sclerosis was graded as follows: 0 = normal AV; 1 = increased echo density; 2 = thickening or calcific deposits > or = 3 mm; and 3 = same as 2 with mildly restricted motion (pressure gradient < 16 mm Hg). Lp(a) levels ranged from < 1 mg/dl to 153 mg/dl. The 25th, 50th, and 75th percentile values were 7, 16, and 28 mg/dl, respectively. Lp(a) levels were significantly higher in women than in men (p < 0.01), and did not increase significantly with age. The prevalence of AV sclerosis (grades 2 and 3) increased significantly with age (p < 0.001). AV sclerosis was present in 65 (36.1%) of 180 subjects with Lp(a) levels > or = 30 mg/dl and in 77 (12.7%) of 604 subjects with Lp(a) levels < 30 mg/dl (p < 0.001). There were no significant differences in the prevalence of AV sclerosis in terms of sex, blood pressure, or levels of total cholesterol, high-density lipoprotein cholesterol, triglycerides, or blood sugar. We conclude that increased serum levels of Lp(a), as well as aging, are closely related to AV sclerosis.

The accuracy and clinical performance of a new compact ambulatory blood pressure monitoring device, the ES-H531.

The validity and clinical performance of the ES-H531, a newly developed ambulatory blood pressure (BP) monitoring device, were evaluated. The validity was assessed by simultaneous comparisons (total of 223 measurements) with the measurements made by two experienced observers using standard mercury column sphygmomanometers in 121 subjects. The clinical performance was evaluated through the number of measurement failures by observation of the cuff equipped site, and tolerability was assessed by administering a questionnaire to 30 of the subjects following completion of 24-h BP monitoring. The differences in systolic and in diastolic BP measured by the standard auscultation method and that measured with the ES-H531 by the Korotkoff method (K method) was 0.9+/-3.7 mm Hg (mean+/-standard deviation) and 0.1+/-3.2 mm Hg, respectively. These values satisfy the accuracy criteria of the American Association of Medical Instruments (AAMI) and accord with the grade of A in the accuracy criteria of the British Hypertension Society (BHS). The mean difference in systolic and in diastolic BP as assessed by the standard auscultation method and with the ES-H531 by the oscillometric method (O method) was 1.1+/-4.6 mm Hg and 2.7+/-5.4 mm Hg, respectively. This accords with grade B in the BHS accuracy criteria. Failures or errors in measurement occurred in 4.4% of the readings. A few subjects experienced discomfort because of noise or pain during measurements. The ES-H 531, a new compact and light weight ambulatory BP monitoring device, offers acceptable validity and sufficient comfort for clinical use.

Power spectral analysis of spontaneous blood pressure and heart rate variability in elderly hypertensives.

To examine the influence of hypertension on cardiovascular variability in elderly subjects, we measured spontaneous beat-to-beat blood pressure (BPV) and heart rate variability (HRV) in elderly subjects with or without hypertension at rest and during tilting. The study group consisted of 23 community-dwelling, male elderly subjects (aged 62-75 years) and was divided into two groups, i.e., a hypertensive group (HT group; n = 11) and normotensive group (NT group; n = 12). According to the modeling and decomposing algorithm of an autoregressive process, we estimated the component power of low-frequency (LF; 0.03-0.15 Hz) and high-frequency components (HF; respiratory frequency) of BPV and HRV by power spectral analysis. We also measured plasma norepinephrine (PNE) levels in the two groups at rest and during tilting. In the HT group, we found that the amplitude of LF-BPV was greater (p < 0.05) and its relative change by postural tilting was smaller (p < 0.05) than those in the NT group. We found no significant difference in the amplitude of LF-HRV and HF-HRV between the two groups, and found no significant response of the amplitude of LF-HRV and HF-HRV to postural tilting. We also found no difference in PNE level between the two groups at rest or during tilting. These results suggest that the regulatory function of sympathetic vasomotor activity assessed by power spectral analysis of BPV is altered in hypertensive elderly subjects, although the influence of hypertension on the autonomic control of the heart is less dominant in the elderly.

Prognostic value of nighttime blood pressure in the elderly: a prospective study of 24-hour blood pressure.

Although it has been suggested in several reports that 24-h ambulatory blood pressure (BP) is a better predictor than casual BP measured in a clinician's office of the incidence of cardiovascular (CV) events, little information is available concerning the prognostic value of nighttime BP in the elderly population. Therefore, to evaluate the clinical implications of the nighttime BP in the elderly, we prospectively followed-up 324 elderly individuals (mean age, 77.2 +/- 7.0 years) who had undergone ambulatory BP monitoring at an annual health examination over a mean follow-up period of 51.5 +/- 22.0 months, and the relationship between BP and CV events was analyzed using Cox's proportional hazard model. For the analysis, 310 participants, excluding 14 subjects who were withdrawn due to non-CV events, were classed into two groups, one consisting of 134 individuals who were undergoing treatment with an anti-hypertensive drug (medicated group) and another consisting of 176 who were not medicated (nonmedicated group). New cardiovascular events developed in 43 cases in the medicated group and in 14 cases in the non-medicated group during the follow-up period. In the medicated group, a linear relationship was observed between BP and the event rates. The hazard ratio for CV events adjusted for age, sex, and other cardiovascular risks was 1.28 (95% confidence interval [CI], 1.05 to 1.54, p< 0.05) for a 10 mmHg increase of 24-h systolic BP. Corresponding values in 24-h diastolic BP, nighttime systolic BP, and nighttime diastolic BP were 1.71 (1.19 to 2.46, p< 0.01), 1.34 (1.13 to 1.58, p< 0.01), and 1.67 (1.20 to 2.31, p< 0.01), respectively. In the non-medicated group, the event rate was least in the subgroup in the second-lowest quartile for nighttime systolic BP, with a slight non-significant increase in the subgroup of the lowest quartile. It was shown that insufficient control of nighttime BP in the elderly with hypertension is associated with the development of CV complications.

Predicting the severity of coronary lesions by the continuous recording method of exercise two-dimensional echocardiography.

We estimated the severity of coronary artery disease by the continuous-recording method of exercise two-dimensional echocardiography (Ex.2DE) in 56 patients with angiographically significant coronary artery stenosis ( > 50% diameter narrowing) who had undergone both Ex.2DE and coronary angiography. Patients were divided into two groups on the basis of findings of coronary angiography: group 1 had 50% to 89% stenosis (n = 24) and group 2 had 90% or greater stenosis (n = 32). The sensitivity and specificity of Ex.2DE for the detection of ischemic segments were 82% and 88%, respectively in the overall patient population. The sensitivity was 67% in group 1 and 94% in group 2. Hyperkinesis occurred at the beginning of exercise in 21 (88%) of 24 patients in group 1 and 15 (47%) of 32 patients in group 2 (p < 0.05). Our findings demonstrated that patients who did not show hyperkinesis at the beginning of exercise had more severe coronary artery disease. Careful observation of serial wall motion during exercise by the continuous-recording method may provide important information about myocardial ischemia.

Nitric oxide synthesis in rat cardiac myocytes and fibroblasts.

We investigated nitric oxide (NO) synthase activity in cultured neonatal rat cardiac myocytes and fibroblasts upon treatment with interleukin 1 beta (IL-1 beta) and lipopolysaccharide (LPS). Incubation of cardiac myocytes for 24 h with IL-1 beta or LPS caused a significant increase in NO and cGMP production. Simultaneous incubation of IL-1 beta with NG-monomethyl-L-arginine or transforming growth factor beta (TGF-beta) completely inhibited the IL-1 beta-induced NO and cGMP production in cardiac myocytes. In contrast, incubation of cardiac fibroblasts for 24 h with IL-1 beta or LPS showed no significant effect on NO or cGMP production. Addition of IL-1 beta decreased the beating rate of cardiac myocytes, but TGF-beta overcame that inhibition. These observations suggest the presence of iNOS in cardiac myocytes, which is an important regulator of contractile function of the heart.

Effect of a Change in the Sleep/Wake Cycle on the Diurnal Variation of Fibrinolytic Parameters.

The mechanism underlying the circadian rhythm of fibrinolysis is not well understood. To evaluate the influences of wakefulness and of the intrinsic circadian rhythm on fibrinolytic activity, we examined diurnal changes (8:00 am vs. 8:00 pm) in plasminogen activator inhibitor-1 (PAI-1) activity, tissue plasminogen activator (t-PA) antigen levels, and t-PA activity, as well as in plasma serum cortisol levels, in 10 healthy males (21 +/- 2 years) for two consecutive days. On the first day, subjects remained awake all day and night. They slept during the daytime (8:30 am to 5:30 pm) on the following day. PAI-1 activity and cortisol levels were significantly decreased, and t-PA activity tended to increase during the daytime on the first day. On the morning following overnight wakefulness, PAI-1 activity and cortisol levels did not return to the levels of the previous morning. On the second day, the afternoon decrease in PAI-1 activity, but not cortisol levels, was still observed, although its magnitude was substantially attenuated. No significant diurnal changes were observed in the levels of t-PA antigen throughout the study period. These findings suggest that the diurnal variation of fibrinolytic activity may be governed by an intrinsic circadian rhythm of PAI-1, which can be modified by a change in the time of wakefulness.