Hirofumi Tomiyama

Estrogen Promotes Early Osteoblast Differentiation and Inhibits Adipocyte Differentiation in Mouse Bone Marrow Stromal Cell Lines that Express Estrogen Receptor (ER) α or β

Although cells of the osteoblast lineage express functional ERs, direct effects of estrogen on bone formation remain obscure. In the present study, we have investigated estrogen effects on osteoblastic and adipocytic differentiation from a mouse bone marrow stromal cell line, ST-2, which had been manipulated to overexpress either human ER (ST2ER )o r ER (ST2ER). Treatment with bone morphogenetic protein-2 increased alkaline phosphatase activity as well as the number of Oil Red O-positive adipocytes, indicating that bone morphogenetic protein-2 stimulated both osteoblastic and adipocytic differentiation from these bipotential cells. In both ST2ER and ST2ER cells, cotreatment with E2 caused enhancement of alkaline phosphatase activity and suppression of lipid accumulation. These effects were completely reversed by an ER antagonist, ICI182780. Therefore, the estrogen regulation occurred in an ER-specific manner but without ER subtype specificity. Moreover, dose response curves of the opposing effects of estrogen on osteoblastogenesis and adipogenesis formed an apparent mirror image, consistent with a reciprocal regulation of differentiation into the two cell lineages. These results demonstrate that estrogen directly modulates differentiation of bipotential stromal cells into the osteoblast and adipocyte lineages, causing a lineage shift toward the osteoblast. Such effects would lead to direct stimulation of bone formation and thereby contribute to the protective effects of estrogen on bone. (Endocrinology 143: 2349 –2356, 2002)

Diastolic Fractional Flow Reserve to Assess the Functional Severity of Moderate Coronary Artery Stenoses Comparison With Fractional Flow Reserve and Coronary Flow Velocity Reserve

BackgroundCoronary blood flow occurs mainly during the diastolic phase of each cardiac cycle and is mainly dependent on diastolic driving pressure, especially in the left anterior descending coronary artery (LAD). We hypothesized that calculation of the ratio of the diastolic driving pressure of a stenotic LAD to its normal value, namely diastolic FFR (d-FFR), might provide precise insight into the mechanism of FFR for assessment of the functional severity of the stenosis. We compared d-FFR with FFR, coronary flow reserve (CFR), and exercise myocardial thallium scintigraphy in an lesion of intermediate severity. Methods and ResultsThe study population consisted of 46 consecutive patients with a moderate stenosis in the LAD in whom simultaneous measurements of aortic pressure, left ventricular pressure, and coronary pressure distal to the stenosis were obtained. Coronary flow velocity was successfully measured with a Doppler guidewire in 37 of the 46 patients. Values for FFR, d-FFR, and CFR in the noninvasive test–positive group were significantly lower than those in the negative group. With cutoff values of 0.75, 0.76, and 2.0 for FFR, d-FFR, and CFR, sensitivities were 83.3%, 95.8%, and 88.2% and specificities were 100%, 100%, and 95.0%, respectively. ConclusionsThe close similarity of the sensitivity and specificity of FFR and d-FFR, around almost identical cutoff values (0.75 versus 0.76), confirms the physiological validity of FFR as a clinical standard. In clinical practice, FFR remains the index of choice for assessment of the functional severity of moderate coronary artery stenoses.

Angiotensin-converting enzyme inhibition improves defective angiogenesis in the ischemic limb of spontaneously hypertensive rats.

OBJECTIVESnNatural angiogenesis has been shown to be impaired in spontaneously hypertensive rats (SHR). The purpose of this study was to determine whether pathological angiogenesis in the setting of tissue ischemia is also impaired in SHR, and to what extent it is modified by angiotensin-converting enzyme (ACE) inhibition.nnnMETHODSnIschemia was induced in the hindlimb of SHR by excision of the femoral artery, after which the animals were randomly assigned to receive low-dose perindopril (sub-antihypertensive, 0.2 mg/kg/day), high-dose perindopril (antihypertensive, 2.0 mg/kg/day), or vehicle for 3 weeks. Wistar-Kyoto rats (WKY) with femoral artery excision served as a control group.nnnRESULTSnTissue ACE activity in SHR was significantly increased compared to WKY (49.4+/-6.2 vs. 34.0+/-14.2 IU/mg, P<0.01). Administration of perindopril significantly reduced ACE activity in SHR (low dose: 12.4+/-2.3; high dose: 11.0+/-2.1 IU/mg, P<0.005). Angiogenesis of the ischemic limb muscles was significantly impaired at 4 weeks in SHR versus WKY as indicated by the lower capillary density in the former (364.5+/-43.0 vs. 463.8+/-63.0/mm(2), P<0.05) as well as the reduced hindlimb perfusion assessed by laser Doppler imaging (0.86+/-0.08 vs. 1.03+/-0.09, P<0.05). Administration of perindopril significantly augmented both the capillary density (low dose: 494.3+/-69.8; high dose: 543.9+/-76.9/mm(2), P<0.005) and the limb perfusion (low dose: 1.06+/-0.15; high dose: 1.05+/-0.12, P<0.05) of the ischemic limb in SHR.nnnCONCLUSIONSnThese findings indicate that pathological angiogenesis in the setting of tissue ischemia is impaired in SHR compared with WKY, and that this impairment can be reversed by ACE inhibition. The angiogenic properties of an ACE inhibitor may benefit patients with essential hypertension presenting with lower limb vascular insufficiency.

Relationship Between Endothelial Function and Fibrinolysis in Early Hypertension

Abnormalities in fibrinolysis, endothelial function, and glucose and lipid metabolism have been reported in hypertension. This study was conducted to examine the interrelationships between fibrinolytic factors, glucose and lipid metabolism, and endothelial function in hypertension. The effects of administering an angiotensin converting enzyme inhibitor, benazepril, were also examined. Blood levels of the following substances were measured in patients with borderline and mild hypertension (n=50, 51+/-19 years) and in age-matched controls (n=10): total cholesterol, triglycerides, tissue plasminogen activator activity and antigen, and plasminogen activator inhibitor type 1 activity and antigen. Insulin sensitivity was assessed by oral glucose tolerance test, and endothelial function was assessed by evaluating changes in diameter of the brachial artery during reactive hyperemia as observed by ultrasonography. Activities of tissue plasminogen activator and plasminogen activator inhibitor type 1 were both elevated in the hypertensive patients. Stepwise multiple regression analysis showed that plasminogen activator inhibitor type 1 antigen correlated with insulin sensitivity, total cholesterol levels, and triglycerides levels (P<.01). Endothelial function was negatively correlated with tissue plasminogen activator activity and antigen (P<.01). The chronic administration of benazepril (5-10 mg/d) for 20 weeks improved insulin sensitivity, endothelial function (6.6+/-3.4-->9.0+/-2.5%, P<.01), and tissue plasminogen activator activity and antigen. These results indicate that abnormalities in fibrinolysis are associated with endothelial dysfunction as well as disorders of glucose and lipid metabolism in patients with borderline and mild hypertension. The treatment of such patients with benazepril appeared to improve the impairment in fibrinolysis and endothelial dysfunction.

Drugs, heart failure and quality of life: what are we achieving? What should we be trying to achieve?

This article is a review of chronic compensated congestive heart failure (CHF), with special reference to its clinical features and pathophysiology and recent advances in pharmacotherapy, including ß-blockers, loop diuretics, ACE inhibitors and angiotensin II receptor antagonists. Clinical problems related to elderly patients and multifaceted aspects of multidisciplinary approaches of medical care to these particular patients are also discussed with special emphasis on the aspect of improved quality of life associated with reduced mortality.Concepts of CHF have greatly changed over the past decades with regard to its pathophysiology, natural progression, mechanisms, causes of death, arrhythmias and treatment goals. Although the current most frequent aetiologies of CHF include coronary heart disease and dilated cardiomyopathy, hypertension has been revisited in a different way, and has been considered of pivotal importance in most recent trends and possibly in future perspectives. Nowadays, however, with the results of improved survival, alleviation of symptoms, improvement in functional capacity and prevention of associated complications including even left ventricular remodelling through various appropriate pharmacotherapies, patients with CHF are used to being physically and psychosocially more active than ever before. Thus, improvement of patients’ quality of life and reduction of mortality have become of prime importance in achieving treatment goals. Another emerging aspect of CHF is aging itself, and special features in the medical care of elderly patients with CHF always have to be taken into consideration in reduction of hospital readmission along with improvement of morbidity and mortality.Despite advances in the treatment of CHF, it remains a common disease with a poor prognosis. Therefore, this review focuses on what we should be trying to achieve in reaching goals to reduce repeated hospital readmission and mortality, and increase social activity and quality of life, especially in elderly patients with CHF. In these clinical settings, educational strategies for patients and their family members should be emphasised. Multidisciplinary interventions by nurses and possibly other contributions from a widely available social support system might be effective in preventing repeated hospital readmissions of elderly patients with CHF. In this regard, special precautions have to be paid in the management of elderly patients to achieve effective treatment goals, and any treatment strategy has to be appropriately determined through a comprehensive assessment of patient clinical profiles. Multidisciplinary approaches to these problems have to be effectively utilised to improve patients’ quality of life, while possibly reducing medical expenses.

Effects of an ACE Inhibitor and a Calcium Channel Blocker on Cardiovascular Autonomic Nervous System and Carotid Distensibility in Patients with Mild to Moderate Hypertension

We investigated the relationship between cardiovascular autonomic nervous system function and carotid arterial distensibility during treatment with an angiotensin converting enzyme inhibitor (derapril) or a calcium channel blocker (manidipine) for hypertension. In 37 patients with hypertension, autonomic function was assessed by heart rate variability and baroreceptor sensitivity using phenylephrine injection. Left ventricular mass index and carotid arterial distensibility were assessed by ultrasound examinations. Before the medication, both baroreceptor sensitivity and heart rate variability correlated with carotid arterial distensibility, but not with left ventricular mass index by multiple regression analysis. Subsequently, patients were randomly allocated into two groups, derapril (n = 18) and manidipine (n = 19) for 20 weeks. At the end of the study, the change in baroreceptor sensitivity correlated with change in carotid arterial distensibility (r = 0.41, P < .05), but not with change in left ventricular mass index. Although derapril and manidipine decreased blood pressure and left ventricular mass index to the same extent, the former improved heart rate variability, baroreceptor sensitivity (5.0 +/- 1.9 --> 5.6 +/- 2.0 msec/mm Hg), and carotid arterial distensibility (2.1 +/- 0.8 --> 2.5 +/- 1.0 %kPa), but the latter did not improve them at all. Thus, impairment of the autonomic balance was related to the impairment of carotid arterial distensibility in hypertension; derapril, but not manidipine, significantly improved these abnormalities.

Left ventricular geometric patterns and QT dispersion in borderline and mild hypertension: their evolution and regression.

To investigate whether QT dispersion increases in borderline and mild hypertension during a longitudinal observation of > 3 years and whether it is improved with medications, left ventricular geometric patterns and QT dispersion were studied with special regard to their longitudinal changes in 85 male borderline and mild hypertensive subjects with left ventricular mass index < 125 g/m2. These subjects were followed for > 3 years without medication. Thirty-two patients with a left ventricular mass index > 125 g/m2 at the end of follow-up period were further observed using antihypertensive drugs for an additional 3 years. Echocardiograms and electrocardiograms were obtained at the beginning and end of the follow-up period. At the end of the follow-up period, subjects were classified into four groups based on ventricular geometric patterns determined by left ventricular mass index and relative wall thickness in diastole. The QT dispersion was greater in patients with concentric hypertrophy (56+/-18 msec) than in patients with normal geometry (41+/-17 msec) (P < .05) and increased significantly in the former group during the follow-up period. After medication, the left ventricular mass index regressed and the QT dispersion decreased (from 55+/-21 to 50+/-26 msec, P < .01) in these patients. Thus, these findings suggest that changes in the QT dispersion reflect both concentric evolution and regression of left ventricular hypertrophy.

The Relationship of Hyperinsulinemic State to Left Ventricular Hypertrophy, Microalbuminuria, and Physical Fitness in Borderline and Mild Hypertension

The relationship of the hyperinsulinemic state to left ventricular hypertrophy, left ventricular geometric patterns, microalbuminuria, and physical fitness were studied in 52 middle-aged unmedicated men with borderline and mild hypertension. Left ventricular mass index and relative wall thickness were assessed by echocardiography. Physical fitness was determined by symptom-limited maximal treadmill stress testings. The urinary concentration of microalbumin and C-peptide was measured in 24-h urine samples by radioimmunoassey. The 24-h urinary C-peptide excretion rate was correlated with left ventricular mass index (r = 0.46), relative wall thickness (r = 0.41), treadmill time (r = -0.35), normalized treadmill time (r = -0.52), systolic blood pressure at peak exercise (r = 0.29), and 24-h urinary microalbumin excretion (r = 0.48). Stepwise multiple regression analysis identified the left ventricular mass index, the 24-h urinary albumin excretion, and the normalized treadmill time as variables in the equation for the 24-h urinary C-peptide excretion. Thus, the hyperinsulinemic state is related to left ventricular hypertrophy, microalbuminuria, and impaired physical fitness in patients with borderline and mild hypertension.

An impaired carotid sinus distensibility and baroreceptor sensitivity alter autonomic activity in patients with effort angina associated with significant coronary artery disease

Baroreceptor sensitivity and carotid sinus distensibility were lower in patients with angina associated with significant coronary artery disease than in patients with vasospastic angina. Baroreceptor sensitivity was significantly correlated with carotid sinus distensibility in both groups of patients.

Effects of short-acting and long-acting loop diuretics on heart rate variability in patients with chronic compensated congestive heart failure.

BACKGROUNDnWe investigated the effects of a short-acting loop diuretic (furosemide) and a long-acting loop diuretic (azosemide) on heart rate variability, fluid balance, and neurohormonal responses in patients with mild to moderate chronic congestive heart failure.nnnMETHODSnNineteen patients with mild to moderate chronic congestive heart failure received furosemide (40 to 60 mg/day) or azosemide (60 to 90 mg/day) for 5 days in a crossover manner. We performed time-domain and frequency-domain analyses of 24-hour Holter electrocardiographic recordings to assess heart rate variability.nnnRESULTSnThe 24-hour urinary sodium excretion was similar during the furosemide and azosemide treatment periods but was significantly greater in the first 2 hours after drug administration during furosemide treatment. Plasma renin activity and the hematocrit level increased and high-frequency power significantly decreased 2 hours after the administration of furosemide only. The standard deviation of all normal R-R intervals and the root mean square of successive differences in the R-R interval were lower with furosemide than with azosemide (P <.05).nnnCONCLUSIONSnFurosemide, a short-acting loop diuretic, has a greater influence on heart rate variability and fluid balance than azosemide, a long-acting loop diuretic, in patients with mild to moderate chronic congestive heart failure.