Determinants of lipid and lipoprotein level in elderly men

In an effort to better understand the relationship existing between lipoprotein pattern and longevity, we studied the lipid and lipoprotein distribution of 94 men over age 80 who lived in a nursing home, and assessed the role of selective mortality, body mass and sex hormone secretion in determining these distributions. High density lipoprotein subfraction and serum testosterone measurements were obtained on subsamples. The main findings were: (a) Presence of a lipoprotein pattern characterized by low LDL (total serum cholesterol: 179.6 ± 36.0 mg/dl; LDL cholesterol: 106.3 ± 31.2 mg/dl) and high HDL₂ cholesterol (18.5 ± 10.2 mg/dl) levels. (b) Occurrence of a positive association between LDL and HDL₃ (r = 0.51, P < 0.01), resulting in an overall high HDL₂/HDL₃ ratio. Mortality over a 6-month period was directly related to LDL level and possibly inversely related to HDL₂ level, suggesting that selective mortality played a major role in determining the pattern observed. Body mass and serum testosterone concentration, which tended to be low, were independently correlated with lipoprotein level, a particularly strong correlation (positive) existed between free testosterone and triglyceride (r = 0.68, P < 0.01). The latter results suggest that changes related to senescence also influenced lipid and lipoprotein levels.     

Reduction of urinary albumin excretion by thromboxane synthetase inhibitor, OKY-046, through modulating renal prostaglandins in patients with diabetic nephropathy

We evaluated the effects of thromboxane synthetase inhibitor, OKY-046, on urinary albumin and prostaglandin (PG) excretion in 14 patients with non-insulin-dependent diabetes mellitus (NIDDM).

Urinary excretion of 6-keto-PGF₁ (a stable metabolite of PGI₂), TXB₂ (a stable metabolite of TXA₂) and PGE₂ in NIDDM patients was comparable with that in control subjects. However, the urinary 6-keto-PGF₁/TXB₂ ratio in NIDDM patients with both micro- and macroalbuminuria was significantly (P < 0.001) lower than that in the controls.

By a single administration of OKY-046 (40 mg, i.v.) to the diabetic patients, urinary TXB₂ excretion significantly (P < 0.05) decreased from 169.7 ± 23.9 to 140.2 ± 17.9 ng/gCr, but urinary 6-keto-PGF₁ and PGE₂ excretion did not change significantly. The urinary 6-keto-PGF₁/TXB₂ ratio thus significantly (P < 0.01) increased from 1.02 ± 0.13 to 1.73 ± 0.41 as associated with significant increments in urine volume (P < 0.05), urinary sodium excretion (P < 0.01) and creatinine clearance (P < 0.05).

Of 14 diabetic patients, 7 with macroalbuminuria (albumin index exceeding 100 mg/gCr) were orally given OKY-046 (600 mg/day) for 8 weeks. After this period, the urinary albumin index significantly (P < 0.05) decreased from 524.9 ± 149.6 to 317.6 ± 90.6 mg/gCr. Urinary PG excretion did not change significantly, although the urinary 6-keto-PGF₁/TXB₂ ratio significantly (P < 0.01) increased from 1.33 ± 0.16 to 2.42 ± 0.65 and decreased to 1.09 ± 0.15 (P < 0.01) following termination of this drug. Similarly, creatinine clearance significantly (P < 0.01) increased, from 56.3 ± 14.1 to 69.4 ± 15.1 ml/min. During the period of 8 weeks, no significant alteration occurred in systemic blood pressure or glycemic control.

In conclusion, OKY-046 has a beneficial effect on albuminuria in diabetic nephropathy by modulating altered renal PGs synthesis, which leads to a change in renal hemodynamics.     

Different effects of two progestins on plasma high density lipoprotein (HDL2) and postheparin plasma hepatic lipase activity

Two progestins with different androgenic activity were compared for their effects on plasma high density lipoproteins and postheparin plasma lipase activities in premenopausal women. Levonorgestrel, a nortestosterone-derived steroid with androgenic activity reduced plasma HDL cholesterol by 17% (P < 0.05) and HDL₂ cholesterol by 30% (P < 0.05), without changing the HDL₃ cholesterol concentration. At the same time the postheparin plasma hepatic lipase activity was increased by 56% (P < 0.01) whereas the lipoprotein lipase was not changed. None of these effects was reproduced during administration of medroxyprogesterone acetate, a progestin with low androgenic activity. The results suggest, first, that the decrease of HDL cholesterol observed during treatment with progestins is related to the androgenic activity of the steroid used, and, second, that the change in HDL (HDL₂) is caused by androgen-induced increase of hepatic lipase activity.     

Influence of endogenous hyperinsulinism on high density lipoprotein2 level in type 2 (non-insulin-dependent) diabetes mellitus and impaired glucose tolerance

We determined the insulin response to an oral glucose ingestion and levels of serum lipoproteins in 25 untreated patients with type 2 diabetes mellitus, in 26 subjects with impaired glucose tolerance (IGT), and in 35 non-diabetic control subjects. The three groups had similar compositions with respect to age and sex distribution. The levels of VLDL triglycende in the subjects with type 2 diabetes or IGT were higher than those in controls. Serum HDL- and HDL₂ cholesterol were significantly decreased in type 2 diabetics, and the subjects with IGT showed a similar tendency. Serum apolipoprotein A-II levels were lower in the male subjects with type 2 diabetes or IGT than in controls. Insulin reponse, i.e., sum of immunoreactive insulin (IRI) levels at basal, 30, 60, 90 and 120 min after a 75-g oral glucose load, negatively correlated to HDL and HDL₂ cholesterol levels (r = −0.396, P < 0.05; r = −0.482, P < 0.001, respectively), and positively correlated to VLDL triglyceride values (r = 0.485, P < 0.001) in the male subjects with type 2 diabetes or IGT. In the female subjects, fasting plasma IRI values significantly correlated to HDL cholesterol (r = −0.496, P < 0.05). There was a significant negative correlation between the concentrations of HDL₂ cholesterol and VLDL trgglyceride. These data show that lipoprotein metabolism, not only in type 2 diabetics, but also in IGT tends to show changes such as decreased HDL₂ cholesterol and increased VLDL triglyceride levels, and which might be related to the hypersecretion of endogenous insulin.     

Glucose and insulin responses to intravenous glucose challenge in relatives of Nigerian patients with non-insulin-dependent diabetes mellitus

We analysed blood insulin and glucose concentrations before and during frequently sampled intravenous glucose tolerance tests (FSIGT) in 2 groups of Nigerian subjects: (A) Control group (n = 18), without a positive family history of diabetes mellitus, and (B) Experimental group (n = 16), comprising age-, sex- and body mass-matched first-degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM). In comparison with Group A subjects, those in Group B had: (i) higher fasting plasma glucose level (mean ± S.E.M., 4.1 ± 0.1 vs. 3.8 ± 0.11 mmol/l, P < 0.05); (ii) similar fasting serum insulin levels (6.7 ± 5.0 vs. 5.8 ± 5.6 mU/l, P = NS); (iii) lower mean incremental area under the first-phase (t = 0–10 min) post-glucose challenge insulin curve (376.9 ± 8.8 vs. 435.6 ± 5.6 mU/min l⁻¹, P < 0.05); (iv) increased incremental area under the second-phase (t = 10–182 min) post-glucose challenge insulin curve (432.9 ± 11.5 vs. 161.3 ± 8.7 mU/min l⁻¹, P < 0.05); (v) reduced K_G rate constant of glucose elimination (0.97 ± 0.12 vs. 1.41 ± 0.12%/min, P < 0.05). These results suggest that the subjects with a positive family history of NIDDM have a reduced beta-cell insulin secretory reserve (from reduced first-phase insulin response), tendency to rebound hyperinsulinemia during the latter phase of the insulin secretory response, a degree of tissue insulin insensitivity (as evident from high fasting plasma glucose despite similar insulin levels) and a diminished glucose disposal rate, in comparison with subjects without a family history of NIDDM. These features predict subsequent development of diabetes and suggest that as in Caucasians, first-degree relatives of Nigerian patients with NIDDM are at greater risk for future development of the disease.     

Reactive oxygen species in essential hypertension and non–insulin-dependent diabetes mellitus

To evaluate whether increased levels of reactive oxygen species (ROS) are involved in the pathogenesis of essential hypertension (EH) and non–insulin-dependent diabetes mellitus (NIDDM), both resting and stimulated levels of intracellular ROS were measured in lymphocytes from patients with EH (n = 10), NIDDM (n = 16) and age-matched healthy individuals (control subjects, n = 19). ROS was monitored with the dye, dihydrorhodamine-123 (DHR; 1 μmol/L) in the presence or absence of superoxide dismutase (superoxide scavenger), sodium azide (singlet oxygen/hydrogen peroxide scavenger), genistein (tyrosine kinase inhibitor), or bisindolylmaleimide (protein kinase C inhibitor). Simultaneous monitoring of cytosolic [Ca²⁺]_i was done with fura-2. Resting ROS levels were significantly higher in NIDDM (4.71 ± 0.25 nmol/10⁶ cells; mean ± SEM, P < .05) compared with EH (4.03 ± 0.22 nmol/10⁶ cells) or controls (4.05 ± 0.15 nmol/10⁶ cells). The formyl-Met-Leu-Phenylalanine-(fMLP)–induced ROS generation was significantly higher in NIDDM (21.92 ± 2.23 nmol/10⁶ cells; P < .05) compared with EH (14.58 ± 1.90 nmol/10⁶ cells) or control (16.06 ± 1.22 nmol/10⁶ cells). The fMLP-induced ROS increase was significantly reduced in the presence of sodium azide in all groups (P < .01) but was largely unaffected in the presence of SOD. Genistein and bisindolylmaleimide significantly inhibited the fMLP-induced ROS in all groups. The fMLP-induced [Ca²⁺]_i increase was significantly higher in NIDDM (71 ± 12 nmol/L, P < .01) compared with EH (42 ± 4 nmol/L) and control subjects (35 ± 3 nmol/L). Phytohemagglutinin was more effective in increasing [Ca²⁺]_i than ROS. It is concluded that ROS may play a role in the metabolic syndrome of NIDDM but not in EH.     

Effects of digitalis on ventricular myocardial and His-Purkinje refractoriness and reentry in man

The effects of digitalis on retrograde conduction and refractoriness of the His-Purkinje system, ventricular myocardium and reentry within the His-Purkinje system were studied in 17 patients using the ventricular extrastimulus (V₂) technique. Studies were performed, before and 30 minutes after intravenous administration of ouabain, 0.01 mg/kg. After treatment with ouabain, there was a significant decrease in the functional refractory period (266 ± 19 to 254 ± 18 msec, P < 0.001), relative refractory period (253 ± 17 to 240 ± 16 msec, P < 0.001) and effective refractory period (242 ± 23 to 231 ± 24 msec, P < 0.005) of the ventricular muscle. In contrast, there was no significant change in retrograde His-Purkinje conduction and refractoriness. The phenomenon of reentry within the His-Purkinje system characterized by the reentrant beat (V₃) at critical retrograde conduction delays in the His-Purkinje system (V₂-H₂) within a narrow range of V₁–V₂ intervals was seen in 10 of 17 patients. Ouabain increased and shifted to the left the zone of reentry within the His-Purkinje system in 7 of 10 patients (36 ± 23 to 55 ± 23 msec, P < 0.001) and decreased it by 10 to 30 msec in the remaining 3 patients. The critical V₂-H₂ (186 ± 29 to 193 ± 27 msec, difference not significant [NS]) and V₁–V₂ (299 ± 30 to 294 ± 36 msec, NS) intervals for reentry did not significantly change after ouabain. However, the minimal V₁–V₂ intervals (266 ± 26 to 253 ± 25 msec, P < 0.025) decreased significantly, whereas the maximal V₂-H₂ intervals (266 ± 40 to 239 ± 37 msec, P < 0.01) increased significantly.

Thus, in the intact human heart, digitalis (1) significantly decreased all measures of ventricular myocardial refractoriness, (2) had no significant effect on retrograde conduction and refractoriness of the His-Purkinje system, and (3) widened the zone of reentry within the His-Purkinje system due to shortening of the functional refractory period of the ventricular muscle with attainment of longer V₂-H₂ delays.     

Inhibition of lipoprotein lipase induced cholesterol ester accumulation in human hepatoma HepG2 cells

It has been suggested previously that lipoprotein lipase may act as a ligand to enhance binding and uptake of lipoprotein particles. In the present study we have examined the capacity of bovine milk lipoprotein lipase to induce intracellular accumulation of triglyceride and cholesterol ester by VLDL (S_f 60–400) isolated from Type IV hypertriglyceridemic subject (HTg-VLDL) in HepG2 cells, independent of its lipolytic activity. We have also attempted to elucidate the cellular receptor mechanisms responsible for these effects. HTg-VLDL-mediated increases in intracellular triglyceride and cholesterol ester were dependent on the presence of an active lipase. Bovine milk lipoprotein lipase (LPL) increases triglyceride mass by 301% ± 28% (P < 0.0005) and cholesterol ester mass by 176% ± 12% (P < 0.0005). These HTg-VLDL-mediated increases in intracellular triglyceride and cholesterol ester did not occur when heat-inactivated lipase was used. Rhizopus lipase could replace LPL and cause equivalent increases in intracellular triglyceride and cholesterol ester (472% ± 61% (P < 0.005) and 202% ± 25% (P < 0.025) respectively vs. control). HTg-VLDL treated with LPL and reisolated also caused equivalent increases (274% ± 18% (P < 0.01) and 177% ± 12% (P < 0.005) for triglyceride and cholesterol ester). LDL also caused increases in intracellular cholesterol ester (189% ± 20% (P < 0.005)), although three times more LDL cholesterol had to be added to achieve the same effect. These LDL-induced increases were effectively blocked by monoclonal antibodies directed against the B,E receptor binding domains of apo B (−97% ± 13% (P < 0.0005) with anti-apo B 5E11 and − 68% ± 13% (P < 0.05) for anti-apo B B1B3) or by anti-B,E receptor antibodies (− 77% ± 7% (P < 0.01) antibody C7). These same antibodies had little effect on the HTg-VLDL + LPL-induced increases in cholesterol ester (+21%, + 15% and − 22% for 5E11, B1B3 and C7, respectively). Monoclonal anti-apo E antibodies also had no effect on LDL-mediated increases in intracellular cholesterol ester, but had a small and significant effect on VLDL-mediated increases in cholesterol ester. However, heparin, which interferes with cell surface proteoglycan interaction, was very effective at blocking HTg-VLDL-mediated increases in cholesterol ester in the presence of LPL (− 86% ± 8% P < 0.0005). Heparin was also effective in the presence of Rhizopus lipase (−79%) or lipolyzed re-isolated HTg-VLDL (−95%). These results suggest that lipoprotein lipase may enhance the uptake process beyond its role in lipolytic remodelling but does not appear to be an absolute requirement. In contrast, heparin had no effect on LDL-mediated cholesterol ester accumulation. Lactoferrin, which inhibits interaction with the low density lipoprotein receptor-related protein (LRP), was also very effective at inhibiting HTg-VLDL increases in intracellular cholesterol ester (− 95% ± 6%, P < 0.01). However, there was no effect of either heparin or lactoferrin on HTg-VLDL-mediated triglyceride accumulation. Thus cell surface heparin sulphate may facilitate intracellular lipid acquisition by providing a stabilizing bridge with the lipoproteins and enhance uptake through receptor-mediated processes such as LRP.     

Central markers of body fat distribution are important predictors of plasma lipids in elderly men and women

We determined the contribution of body fat distribution, peak VO₂, fat mass, and dietary intake to variation in plasma lipids in elderly individuals. Volunteers were a healthy cohort of older Caucasian women (n = 75, mean age ± SD, 72 ± 5 years) and older men (n = 101, 72 ± 5 years). We determined fat mass from underwater weighing, fat patterning from waist circumference, as well as peripheral and truncal skinfolds, exercise capacity from peak VO₂, and dietary intake from three-day food diaries. Plasma lipid levels were measured in the fasting state and included total cholesterol, high density lipoprotein (HDL-C), low density lipoprotein (LDL-C), and fasting triglycerides. Older women weighed less than older men, but had higher fat mass, truncal, and peripheral skinfolds. Waist circumference and peak VO₂ were lower in older women than older men. Older women had higher total cholesterol (217 ± 31 vs. 197 ± 30; p < 0.01), HDL-C (54 ± 12 vs. 49 ± 14; p < 0.05), and LDL-C (133 ± 26 vs. 121 ± 27; p < 0.01) when compared with older men. No gender differences were noted in fasting triglycerides. Truncal skinfolds were the best predictor of plasma lipids in older men, accounting for between 9% and 30% (r(²) of the variation in plasma lipids. Similarly, in older women, central markers of fatness (i.e., waist circumference and truncal skinfolds) were the best predictors of plasma lipids (r² = 3% to 24%). Total fat mass, peak VO₂ and dietary intake were not independent predictors of plasma lipids in older men and women. Indices of central body fatness, rather than total fat mass, peak VO₂ or dietary intake are stronger predictors of plasma lipids in healthy older men and women.     

Regression of left ventricular hypertrophy by AT1 receptor blockade in renal transplant recipients

AT₁ receptor antagonists control blood pressure (BP) effectively and reduce left ventricular hypertrophy in patients with essential hypertension. Because left ventricular hypertrophy is very common in renal transplant recipients, we examined the cardiovascular effects and the safety profile of the AT₁ receptor antagonist losartan in hypertensive renal transplant recipients. In 20 renal transplant recipients with stable renal graft function 50 mg of losartan was added to the preexisting antihypertensive treatment (no angiotensin-converting enzyme inhibitors) at least 6 months after renal transplantation. Twenty-four–hour ambulatory BP, two-dimensional-guided M-mode echocardiography, and duplex sonography, as well as renal function, red blood cell count, cyclosporine A and FK 506 levels, erythropoetin, and angiotensin II concentration were determined at baseline and after 6 months of therapy. With 24-h ambulatory BP measurement, systolic blood pressure (SBP) was reduced by 7.5 ± 2.4 mm Hg and diastolic blood pressure (DBP) by 4.5 ± 1.8 mm Hg (P < .01 and P < .05, respectively). Posterior, septal, and relative wall thickness decreased by 0.95 ± 0.2 mm, 0.91 ± 0.2 mm and 0.04 ± 0.01 mm, respectively (all P < .001). Left ventricular mass index decreased by 18.1 ± 4.7 g/m² (P < .01). Ejection fraction and midwall fractional fiber shortening as systolic parameters and the relation of passive-to-active diastolic filling of the left ventricle were unaltered. Serum creatinine and cyclosporine A concentration remained stable in all patients. Hemoglobin and hematocrit decreased by 1.0 ± 0.3 g/dL and 3.6% ± 0.9%, respectively (P < .002 and P < .001) without a change in serum erythropoetin level. In renal transplant recipients the AT₁ receptor antagonist losartan reduces left ventricular hypertrophy without altering systolic or diastolic function. It is safe with regard to renal function and immunosuppression, but slightly decreases hemoglobin level.     

The effect of PGI2 analogue on vascular endothelial function and platelet aggregation in patients with NIDDM

The effect of the short-term administration of beraprost sodium, an analogue of prostaglandin I₂ (PGI₂), on the function of vascular endothelial cells and platelet in non-insulin-dependent diabetes mellitus (NIDDM) patients was investigated. Seven nonobese NIDDM patients with microalbuminuria were recruited for this study. They received a dose of 20 μg of beraprost sodium three times daily for 1 month. Before and after this treatment, various factors concerning functions of vascular endothelial cells and platelet were measured. Treatment with PGI₂ analogue caused a decrease in basal levels of plasma lipoprotein (a) from 16.8 ± 5.3 to 13.2 ± 4.4 mg/dL (p < 0.05), immunoreactive-(i-)endothelin from 2.4 ± 0.3 to 1.6 ± 0.2 pg/mL, and i-thrombomudulin from 9.3 ± 3.7 to 7.9 ± 3.0 FU/L, respectively, and caused a significant increase in basal plasma i-tissue type plasminogen activator (tPA) from 5.3 ± 0.7 to 8.3 ± 1.5 ng/mL (p < 0.01). This treatment also increased maximum response of i-tPA induced by desmopressin infusion. Platelet aggregation due to ADP was inhibited in five of six patients after this treatment. In conclusion, treatment with PGI₂ analogue caused a decrease in the presumed promoting factors of angiopathy such as lipoprotein (a) and endothelin and an increase in the protecting endothelial factor of angiopathy, tissue type plasminogen activator in patients with NIDDM. And immunoreactive thrombomodulin levels which reflect the vascular endothelial cell injury tended to decrease with the treatment. Therefore, it is suggested that this treatment preserves the vascular endothelial function in diabetes.     

Improved right ventricular systolic time intravals after digitalis in patients with cor pulmonale and chronic obstructive pulmonary disease

Although digitalis has been used to treat patients with cor pulmonale secondary to chronic obstructive pulmonary disease, its effect on right ventricular performance has not been conclusively determined. This study assessed the effects of acute digitalization on measurement of right ventricular systolic time intervals in patients with chronic obstructive pulmonary disease and cor pulmonale. The intervals were recorded before and 40 minutes after administration of ouabain, 1 mg intravenously, in nine men (mean age 58 ± 5 [standard deviation] years) with chronic obstructive pulmonary disease (mean maximal mid expiratory flow rate 0.29 ± 0.08 1 liters/sec) and electrocardiographic evidence of right ventricular hypertrophy.

Ouabain produced significant reductions in right ventricular systolic time intervals, including the right ventricular preelection period (from 117 ± 23 to 102 ± 16 msec; P < 0.01), right ventricular ejection time index (from 397 ± 33 to 375 ± 24 msec; P < 0.01) and mean Q-P₂ index (from 509 ± 23 to 474 ± 8 msec; P < 0.001). In eight patients with simultaneously measured left ventricular systolic time intervals, similar changes were observed, including shortening of the left ventricular preejection period index (from 135 ± 9 to 117 ± 11 msec; P < 0.01), ejection time index (from 395 ± 18 to 379 ± 20 msec; P < 0.01), and the mean Q-A₂ interval (from 530 ± 16 to 495 ± 16 msec; P < 0.001). There were no significant changes in aortic or pulmonary arterial pressures. The results demonstrate that acute administration of digitalis produces significant improvement in right ventricular performance in patients with chronic obstructive pulmonary disease and cor pulmonale. The simultaneous shortening of right and left ventricular systolic time intervals is of comparable magnitude.     

CETP is a determinant of serum LDL-cholesterol but not HDL-cholesterol in healthy Japanese

Cholesteryl ester transfer protein (CETP) is one of the factors that regulate plasma levels of HDL-cholesterol. To identify the factors that may regulate CETP activity, and to determine to what extent CETP is correlated with physiologic concentrations of lipoprotein, we performed an epidemiologic study in 586 healthy volunteers (317 males and 269 females, mean age 52.2 ± 10.9 years). CETP activity in these subjects was 192.96 ± 48.73 (mean ± S.D.) nmol/ml/h and distributed to a wide range (60–450 nmol/ml/h). Using multiple regression analysis, we found significant positive correlations between CETP activity and LDL-cholesterol (P < 0.03), apolipoprotein (apo) E (P < 0.005) and LCAT activity (P < 0.001). CETP activities showed significant negative correlation with apo A-I (P < 0.03). However, CETP activity showed no significant correlation either with HDL cholesterol or with apo B. One-way layout analysis of variance showed that alcohol drinking and cigarette smoking significantly reduced CETP activity, but there was no significant association between CETP activity and body mass index. Although CETP activities were significantly higher in females than in males (P < 0.001), multiple regression analysis showed no correlation between CETP activity and age in either the males or the females. Our results suggest that CETP activity regulates the concentration of apo A-I and LDL-cholesterol, and that such activity may be influenced by gender, alcohol consumption and cigarette smoking.     

Reduced platelet serotonin content and release in familial hypercholesterolaemia

Plasma and platelet serotonin (5-HT) concentrations, and resting and collagen-induced 5-HT release in platelet-rich plasma were studied in normal and familial hypercholesterolaemic (FH) subjects. Platelet 5-HT concentrations were significantly reduced (−37%, P<0.01) in FH patients whilst mean plasma concentrations, although increased, were not significantly different from those in normal subjects. Platelet 5-HT correlated negatively with plasma cholesterol when the data for normal subjects and FH patients were combined (r=−0.48, P=0.005). It also correlated negatively with low-density lipoprotein (LDL) (FH data, r=−0.59, P=0.03; normal and FH data, r=−0.49, P=0.004) but positively with high-density lipoprotein (HDL) (FH, r=0.79, P=0.001; normal and FH, r=0.37, P=0.03). Collagen (5–160 μg/ml) stimulated platelet 5-HT release occurred in a concentration-dependent manner. In FH patients stimulated 5-HT release was reduced (10 μg/ml collagen, −40%, P<0.05) and accompanied by increased collagen EC₅₀ values (P<0.02). Resting 5-HT release was increased substantially in FH patients but not significantly. Our data provide evidence for a relationship between circulating cholesterol and platelet serotonergic mechanisms. It is proposed that abnormalities relating to platelet-plasma 5-HT dynamics, perhaps due to enhanced platelet activity or decreased platelet uptake, may contribute to the cardiovascular complications in FH.     

Association between hematological parameters and metabolic syndrome components in a Chinese population

Insulin resistance, an essential core contributing to the metabolic syndrome (MS), has been demonstrated in some studies to be associated with white blood cell (WBC) or red blood cell (RBC) counts. The present study was undertaken to assess systemically the relationship between WBC or RBC counts and various clinical features of MS in a large Chinese population at Taiwan. A total of 4938 subjects (2891 men and 2047 women with a mean age of 50.1±12.6 years), who had attended health examination at this hospital were enrolled. The Adult Treatment Panel III (ATP III) definition of MS components was adopted in this study with the exception of the definition of obesity. This was defined as body mass index (BMI) greater than 27 kg/m². Overall, 14% had high serum total triglyceride (TG), 8% had low high-density lipoprotein (HDL) cholesterol, and 18% were obese. WBC counts showed a statistically significant (P<.001) correlation with TG (r=.265), HDL(r=−.187), fasting glucose (r=.084), and BMI (r=.172) but not with blood pressure levels. In addition, RBC counts correlated significantly (P<.001) with TG (r=.250), HDL(r=−.269), fasting glucose (r=.098), and BMI (r=.228). WBC and RBC counts in subjects grouped according to the presence of 0, 1, 2, and ≥ 3 features of MS were 6268±1633, 6555±1782, 6995±1880, and 7185±1696 cells/mm³, and 4.63±0.56×10⁶, 4.73±0.54×10⁶, 4.84±0.60×10⁶, and 4.91±0.55×10⁶ cells/mm³, respectively (P for trend <.001). Subjects in the highest quartile of WBC or RBC counts demonstrated a three- or twofold increase, respectively, in the odds ratio for MS with 3 or more metabolic features compared to subjects in the lowest quartile of WBC or RBC counts. Increased WBC and RBC counts, albeit normal, were associated with a variety of MS features in a Taiwan Chinese population, suggesting that hematological parameters could potentially be used as indicators of this syndrome.     

Pulse waveform analysis of arterial compliance: relation to other techniques, age, and metabolic variables

T o assess the physiologic and clinical relevance of newer noninvasive measures of vascular compliance, computerized arterial pulse waveform analysis (CAPWA) of the radial pulse was used to calculate two components of compliance, C1 (capacitive) and C2 (oscillatory or reflective), in 87 normotensive (NlBP, n = 20), untreated hypertensive (HiBP, n = 21), and treated hypertensive (HiBP-Rx, n = 46) subjects. These values were compared with two other indices of compliance, the ratio of stroke volume to pulse pressure (SV/PP) and magnetic resonance imaging (MRI)–based aortic distensibility; and were also correlated with demographic and biochemical values.

The HiBP subjects displayed lower C1 (1.34 ± 0.09 v 1.70 ± 0.11 mL/mm Hg, significance [sig] = .05) and C2 (0.031 ± 0.003 v 0.073 ± 0.02 mL/mm Hg, sig = .005) than NlBP subjects. This was not true for C1 (1.64 ± 0.08 mL/mm Hg) and C2 (0.052 ± 0.005 mL/mm Hg) values in HiBP-Rx subjects. The C1 (r = 0.917, P < .0001) and C2 (r = 0.677, P < .0001) were both closely related to SV/PP, whereas C1 (r = 0.748, P = .002), but not C2, was significantly related to MRI-determined aortic distensibility.

Among other factors measured, age exerted a strong negative influence on both C1 (r = −0.696, P < .0001) and C2 (r = −0.611, P < .0001) compliance components. Positive correlations were observed between C1 (r = 0.863, P = .006), aortic distensibility (r = 0.597, P = .19) and 24-h urinary sodium excretion, and between C1- and MR spectroscopy-determined in situ skeletal muscle intracellular free magnesium (r = 0.827, P = .006), whereas C2 was inversely related to MRI-determined abdominal visceral fat area (r = −0.512, P = .042) and fasting blood glucose (r = −0.846, P = .001).

Altogether, the close correspondence between CAPWA, other compliance techniques, and known cardiovascular risk factors suggests the clinical relevance of CAPWA in the assessment of altered vascular function in hypertension.     

Dynamic change in collateral flow associated with myocardial ischemia in humans

Background: This study sought to investigate how collateral flow changes during myocardial ischemia in patients. Methods: Myocardial contrast echocardiography (MCE) and rapid atrial pacing were performed in 20 patients with angiographically evidenced coronary collaterals from the right coronary artery (RCA) to the occluded left anterior descending coronary artery. Sonicated contrast medium was injected into the RCA before and immediately after atrial pacing to determine the peak background-subtracted contrast intensity (PI) in the collateral territory (PIA) and its ratio to PI in the control territory (PI ratio) as parameters of collateral blood flow. Lactate production in the coronary circulation during pacing was determined to assess myocardial ischemia in the collateral territory. Results: PIA showed a significant correlation with regional wall motion either before (r(squared)=−0.64, P<0.01) or after pacing (r(squared)=−0.65, P<0.01). Similarly, PI ratio was significantly correlated with regional wall motion either before (r(squared)=−0.54, P<0.05) or after pacing (r(squared)=−0.64, P<0.01). Rapid atrial pacing decreased both PIA and PI ratio significantly greater in patients with lactate production than in those without (PIA: −67±53 vs. −15±34%, P<0.05; PI ratio: −68±49 vs. −8.2±32%, P<0.05, respectively), while neither PIA nor PI ratio differ between the two groups of patients before pacing (PIA: 13.8±19. vs. 16.2±13.3U, P=0.75; PI ratio: 0.70±0.71 vs. 0.87±0.65, P=0.58, respectively). Conclusions: We concluded that (1) collateral flow determined by MCE was closely associated with regional cardiac function, and (2) not the amount of collateral flow at rest, but pacing-induced change of collateral flow seemed to be a determinant of regional ischemia in patients with coronary collaterals.     

Diadenosine Polyphosphates’ Action on Calcium and Vessel Contraction

The effects of the endogenous, platelet-derived vasoactive compounds, diadenosine tetraphosphate (AP₄A), diadenosine pentaphosphate (AP₅A), and diadenosine hexaphosphate (AP₆A) on the vasoconstriction of isolated rat renal resistance vessels and rat aortic strips were measured using a vessel myograph. In addition, the effects of AP₄A, AP₅A, and AP₆A on the cytosolic free calcium concentration ([Ca²⁺]_i) were evaluated in cultured rat vascular smooth muscle cells (VSMC) using the fluorescent dye technique. Diadenosine polyphosphates dose-dependently increased the force of renal resistance vessels and isolated aortic strips. The administration of 10 μmol/L AP₄A, AP₅A, or AP₆A significantly increased the force of isolated renal resistance vessels by 3.48 ± 0.43 mN (n = 8), 2.14 ± 0.40 mN (n = 12), or 2.70 ± 0.31 mN (n = 11, each P < .01 compared with resting tension), respectively. The administration of 10 μmol/L AP₄A, AP₅A, or AP₆A significantly increased the force of isolated aortic strips by 2.45 ± 0.97 mNewton (n = 10), 2.70 ± 0.30 mN (n = 6), or 1.48 ± 0.20 mN (each P < .01 compared with resting tension), respectively. The administration of 10 μmol/L AP₄A, AP₅A, or AP₆A significantly increased [Ca²⁺]_i in VSMC to a peak concentration of 314 ± 60 nmol/L (n = 6), 247 ± 25 nmol/L (n = 15), or 332 ± 100 nmol/L (n = 5), respectively (each P < .01 compared with resting value). Both the diadenosine polyphosphate-induced vasoconstriction and [Ca²⁺]_i increase was significantly reduced in the absence of extracellular calcium or after administration of a specific inhibitor of P2 purinoceptors. It is concluded that diadenosine polyphosphates increase [Ca²⁺]_i and hence cause vessel constriction.     

Hormonal control of glucose production and pyruvate kinase activity in isolated rat liver cells: influence of hypothyroidism

Hormonal control of glucose production and of -pyruvate kinase activity has been measured in isolated liver cells from fed control and thyroidectomized rats. In hypothyroid rats, sensitivity to isoproterenol as measured by these parameters was increased: the apparent K_0.5 for isoproterenol-induced stimulation of glucose production decreased from 8.0 ± 3 × 10⁻⁶ M in control rats to 2.0 ± 0.2 × 10⁻⁸ M in hypothyroid rats (P < 0.001) and the apparent K_0.5 for inhibition of -pyruvate kinase was 5 ± 2 X 10⁻⁷ M vs. 7 ± 2 × 10⁻⁹ M (P < 0.001) in control and thyroidectomized rats, respectively. Utilisation of specific adrenergic antagonists confirmed increased β-adrenergic responsiveness in hypothyroid rats. This phenomenon was not reversed by 3 days of T₃ treatment (10 μg/100 g body weight). Sensitivity to the -agonist was unchanged by thyroid status. Stimulation of glucose production and inhibition of -pyruvate kinase activity by glucagon and their reversal by insulin were not affected by hypothyroidism. The dose-response curve to vasopressin and its maximal effect measured on stimulation of glucose production were unchanged in thyroidectomized rats. Thus, hypothyroidism produces a specific enhancement of liver β-adrenergic responsiveness without affecting sensitivity to glucagon, insulin and vasopressin.     

Hemodynamic results of percutaneous aortic balloon valvuloplasty as assessed by sequential Doppler echocardiographic studies

We determined the sequential hemodynamic changes after percutaneous aortic balloon valvuloplasty by means of two-dimensional and Doppler echocardiographic examinations in 25 patients immediately before, immediately after, and 24 to 36 hours after valvuloplasty. An aortic valve area was determined at all three time periods by using the continuity equation from the Doppler velocity profiles. The aortic valve area by Doppler echocardiography immediately before valvuloplasty correlated with that determined by cardiac catheterization (r = 0.85, SEE = 0.08 cm²). The mean aortic valve gradient by Doppler echocardiography was 50 ± 22 mm Hg before the procedure, decreasing to 29 ± 12 mm Hg (P < 0.001), with a small, but significant, increase 1 day later to 33 ± 13 mm Hg (P < 0.001). The mean subvalvular velocity increased from 0.44 ± 0.13 to 0.52 ± 0.15 m/sec immediately after valvuloplasty (P < 0.001), increasing further to 0.60 ± 0.16 m/sec 1 day later (P < 0.001). The resultant aortic valve area increased from 0.45 ± 0.11 to 0.73 ± 0.18 cm² immediately after (P < 0.05). One day later, the aortic valve area increased further to 0.86 ± 0.19 cm² (P < 0.05). Because of the dynamic changes occurring during the first 24 to 36 hours after balloon valvuloplasty, hemodynamic measurements taken immediately after the procedure may underestimate the efficacy of this technique.