Yoram Levo

The effects of hormone replacement therapy in normal postmenopausal women: Measurements of Doppler-derived parameters of aortic flow

In this study the effects of hormone replacement therapy on cardiac function in healthy postmenopausal women were evaluated by Doppler echocardiography that was performed before (T1) and 2.5 months after the initiation of hormone replacement therapy (T2) in the peak estrogenic phase. The following parameters of aortic flow were measured: peak flow velocity, acceleration time, and ejection time. Additional parameters were calculated: flow velocity integral and mean acceleration. The study group included 24 postmenopausal women aged 43 to 60 years (mean 51.6 years). The control group consisted of 19 postmenopausal women aged 46 to 60 years (mean 53.5 years) who were not receiving hormone replacement therapy and who underwent the same evaluation. There were no changes in all Doppler parameters between T1 and T2 in the control group. However, in the study group there were significant increases in peak flow velocity (108.3 +/- 16.7 cm/sec at T1 vs 123 +/- 20.7 cm/sec at T2; p = 0.002), flow velocity integral (17.7 +/- 3.9 vs 21.5 +/- 4.7 cm; p = 0.0003), mean acceleration (11.5 +/- 1.9 vs 13.1 +/- 2.6 m/sec/sec; p = 0.001), and ejection time (324 +/- 37.6 vs 348.8 +/- 40.7 msec; p = 0.002). There was no change in acceleration time (94.8 +/- 6.6 vs 95 +/- 10.9 msec). These results demonstrate that estrogens increase both stroke volume and flow acceleration. The latter probably reflects a combination of enhanced inotropism and vasodilatation. We assume that the cardioprotective effect of hormone replacement therapy in postmenopausal women may be due not only to changes in lipid profile but also to direct effects of estrogens on central and peripheral hemodynamic parameters.

Predictors and long-term prognostic significance of recurrent infarction in the year after a first myocardial infarction

This study was undertaken to examine whether clinical factors predict reinfarction within 1 year of a first acute myocardial infarction (AMI) and to quantify the subsequent influence of reinfarction on long-term mortality. Data from 3,695 patients with a first AMI included in the Secondary Prevention Reinfarction Israeli Nifedipine Trial Registry were analyzed. The 1-year reinfarction incidence was 6.0% (220 of 3,695) and in-hospital mortality during reinfarction was 31%. Patients with reinfarction were older (63.0 vs 60.8 years) at entry. The independent clinical predictors for 1-year reinfarction were (adjusted relative odds): peripheral vascular disease (2.12), anterior location of the first AMI (1.62), angina before the first AMI (1.53), congestive heart failure on admission (1.34), diabetes (1.33), systemic hypertension (1.28) and age increment (1.13). One-year reinfarction rate increased from 4.0% in patients with 0 or 1 risk factor to 23.3% in patients with 5 to 6 risk factors (p < 0.0001). Patients with reinfarction had significantly increased 1- and 5-year mortality compared with those who had no reinfarction (11.8 vs 5.3% and 40.1 vs 20.3%, respectively, p < 0.001). Recurrent AMI within 1 year was the most powerful predictor of long-term (mean 5.5 years) total mortality (adjusted relative risk = 4.76).

Cutting Edge: Anti-Inflammatory Properties of Low Levels of IFN-γ

Activation of naive T and B cells occurs only within the context of organized lymphoid tissue. Thus, the continuous recirculation of mature lymphocytes is crucial for the development of primary immune response to foreign Ags. We have previously shown that low levels of IFN-γ inhibit homing of B cells to the secondary lymphoid organs. In this study, we demonstrate that similarly low doses of IFN-γ down-regulate integrin-mediated adhesion and migration of naive T and Th2 cells, and have a profound effect on the in vivo homing of naive T cells to the lymph nodes. Moreover, we show that these low doses of IFN-γ have anti-inflammatory effects in an in vivo asthma model. Thus, in contrast to the proinflammatory effects of IFN-γ at relatively high concentrations, low dose IFN-γ appears to exert global suppressory effects on T cell trafficking and may have clinical application as an anti-inflammatory agent.

Exercise echocardiography in postmenopausal hormone users with mild systemic hypertension

Rest and exercise echocardiography (at dynamic and isometric exercise) were performed in 30 postmenopausal women (aged 54 +/- 4 years) with borderline to mild hypertension. They were then divided into 2 groups: 17 women who started oral hormone replacement therapy (0.625 mg/day conjugated estrogens or 2 mg/day estradiol) and a control group of 13 nonusers. After 6 to 9 months, a second echocardiography was performed in 26 women (4 withdrew). There were only a few changes in values obtained in the 12 controls at the end of follow-up compared with baseline. Primarily, these changes included a slight decrease in systolic blood pressure at rest and on exercise. Several significant morphologic and hemodynamic alterations appeared in 14 hormone users. Left ventricular cavity dimensions and mass became smaller: mean end-diastolic diameter decreased from 45.9 +/- 3 mm at baseline to 44.4 +/- 3 mm at study termination (p = 0.007). The corresponding values for end-systolic diameter were 25.8 +/- 4 mm and 23.9 +/- 4 mm (p = 0.006); for left atrium diameter, it was 34.5 +/- 4 mm and 32.5 +/- 4 mm (p = 0.001); for left ventricular wall width, it was 19.9 +/- 2 mm and 19.3 +/- 2 mm (p = 0.02); for left ventricular mass, it was 197 +/- 28 g and 179 +/- 32 g (p = 0.006). The resting aortic blood flow velocity and acceleration increased: 119 +/- 18 cm/s before therapy versus 129 +/- 23 cm/s while on hormone substitution (p = 0.04), and 13.6 +/- 3 m/s2 versus 16.5 +/- 4 m/s2 (p = 0.008), respectively. Mean rest to peak exercise systolic blood pressure difference became smaller after hormones: 39 +/- 19 mm Hg versus 28 +/- 13 mm Hg (p = 0.03) during dynamic exercise, and 43 +/- 22 mm Hg versus 25 +/- 13 mm Hg (p = 0.004) during isometric exercise. The above data probably indicate that with hormone replacement therapy, there is an improvement in cardiac function both at rest and during exercise.

The effects of sublingual estradiol on left ventricular function at rest and exercise in postmenopausal women: an echocardiographic assessment.

To evaluate the acute hemodynamic effects of 4 mg estradiol given sublingually. Design Rest and exercise echocardiographies were performed prior to estradiol administration. Then, another set of tests was done post-dose: rest examination at 1 h post-dose, isometric exercise at 65 min post-dose, and dynamic exercise at 100 min post-dose. Results The administration of 4 mg sublingual estradiol to 24 postmenopausal women (aged 48–58 years) was followed 60 min post-dose by a surge in mean estradiol serum levels (1759 ± 704 pg/ml). At rest a slight drop in systolic and diastolic blood pressure was measured after estrogen ingestion: 132 ± 24 mm Hg versus 127 ± 21 mm Hg, p < 0.05; 83 ± 11 mm Hg versus 78 ± 10 mm Hg, p < 0.02. There were no changes in resting heart rate, double product, or vascular resistance. The left heart cavities became smaller: the left atrium diameter decreased from 33.7 ± 4 mm to 32.3 ± 4 mm, p < 0.01; the end-systolic diameter decreased from 24.9 ± 3 mm to 23.6 ± 4 mm, p < 0.01; the end-diastolic diameter decreased from 44.5 ± 4 mm to 42.7 ± 4 mm, p < 0.01. The peak aortic blood flow velocity fell from 120 ± 19 cm/s to 116 ± 22 cm/s (p < 0.05), and the flow velocity integral fell from 26.3 ± 4 cm to 24.9 ± 5 cm (p < 0.01); the cardiac output underwent a small change, with borderline significance: 7 ± 2 L/min versus 6.7 ± 2 L/min, p = 0.06. Only minor changes in the hemodynamic and echocardiographic parameters were recorded after estrogen for both isometric and dynamic exercises. Analyses were also made for two subgroups: 13 normotensive women were compared with 11 hypertensive women. The post-estrogen decreases in resting blood pressure and in peak blood velocity were observed only in the hypertensive subjects, whereas the changes in heart dimensions and in flow velocity integral were the same in both subgroups. Conclusions Sublingual estradiol was associated with acute hemodynamic alterations mainly at rest but also after exercise. (Menopause 1998;5:79–85. ± 1998, The North American Menopause Society.)

Menopause-Related Changes in Left Ventricular Function in Healthy Women

Using technetium scans, this study was aimed at examining possible changes in left ventricular function related to the natural process of cessation of ovarian estrogen production. Fourteen healthy postmenopausal women, divided into two groups according to the time-lapse from menopause (A > 3 years; B < 5 years), underwent a technetium heart scan. The two groups did not differ in heart rate, blood pressure, double product, systemic vascular resistance and cardiac index. The mean end-systolic volume in group A was 14.9 and 25.7 ml/m2 in group B (p = 0.003). The mean pressure/volume ratio was significantly higher in group A than in group B (8.6 vs. 4.7 mm Hg/ml/m2, p = 0.02). Peak ejection rate and peak filling rate were also significantly greater in group A compared to group B (3.3 vs. 2.8 end-diastolic volumes/s, p = 0.02; 2.8 vs. 2.1 end-diastolic volumes/s, p = 0.001, respectively). Our findings suggest that women at an early phase of menopause have a higher degree of myocardial contractility than women of a similar age whose menopause is of longer duration.

Rosiglitazone improves aortic arginine transport, through inhibition of PKCα, in uremic rats

Peroxisome proliferator-activated receptor (PPAR) agonists were shown to inhibit atherosclerosis through augmentation of endothelial nitric oxide synthase (eNOS) activity. In addition, rosiglitazone exerts a beneficial effect in chronic renal failure (CRF). Since l-arginine transport by CAT-1 (the specific arginine transporter for eNOS) is inhibited in uremia, we aimed to explore the effect of rosiglitazone on arginine transport in CRF. Arginine uptake by aortic rings was studied in control animals, rats, 6 wk following 5/6 nephrectomy (CRF) and rats with CRF treated with rosiglitazone. The decrease of arginine transport in CRF was prevented by rosiglitazone. Immunobloting revealed that CAT-1 protein was decreased in CRF but remained unchanged following rosiglitazone administration. Protein content of the membrane fraction of PKCalpha and phosphorylated CAT-1 increased significantly in CRF, effects that were prevented by rosiglitazone. PKCalpha phosphorylation was unchanged but significantly attenuated by rosiglitazone in CRF. Ex vivo administration of phorbol-12-myristate-13-acetate to rosiglitazone-treated CRF rats significantly attenuated the effect of rosiglitazone on arginine uptake. The decrease in cGMP response to carbamyl-choline (eNOS agonist) was significantly attenuated by rosiglitazone in CRF. Western blotting and immunohistochemistry analysis revealed that protein nitration was intensified in the endothelium of CRF rats and this was attenuated by rosiglitazone. In conclusion, rosiglitazone prevents the decrease in arginine uptake in CRF through both depletion and inactivation of PKCalpha. These findings are associated with restoration of eNO generation and attenuation of protein nitration and therefore may serve as a novel mechanism to explain the beneficial effects of rosiglitazone on endothelial function in uremia.

AORTIC DISSECTION MANIFESTED AS FEVER OF UNKNOWN ORIGIN

Aortic dissection is accompanied by fever in about one third of the patients. However, fever of unknown origin as the predominant manifestation of aortic dissection seems to be extremely rare. A review of the English literature revealed only 3 patients characterized by fever as the principal sign of aortic dissection. Herein an additional patient is reported. All 4 patients presented with pain or discomfort in the chest, back or abdomen, followed by persistent fever, lasting 5-11 weeks and associated with anemia and a high sedimentation rate. The outcome was favorable in all cases regardless of the location of the dissection or the type of treatment.

Reduced production of tumor necrosis factor by mononuclear cells in hairy cell leukemia patients and improvement following interferon therapy.

In 16 patients with hairy cell leukemia (HCL) there was a marked reduction in the production of cytotoxins (CTXs) by peripheral blood mononuclear leukocytes in response to stimulation in vitro by phytohemagglutinin (PHA), 4β‐phorbol‐12‐myristate‐13‐acetate (PMA), or Sendai virus. CTX yields of 23.5 ± 21.5 U/ml, 15 ± 18 U/ml, and 12.1 ± 12.1 U/ml were obtained in response to PHA, PMA, and Sendai virus, respectively, as compared with corresponding yields of 207.3 ± 93.1, 154 ± 37.4, and 205.2 ± 62.4 in healthy controls. The extent of reduced production of CTXs appeared to be correlated with the severity of the disease. Systemic interferon (IFN) administered to four patients caused CTX production to improve in response to PHA (147.5 ± 55.1 U/ml compared with pretreatment values of 14.1 ± 6 U/ml, P < 0.05). However, CTX production in response to Sendai virus remained low. The extent to which CTX production by hairy cell leukemia mononuclear cells was reduced was proportionate to the observed decrease in monocyte counts. However, the degree to which CTX production improved after IFN treatment was significantly greater than the observed increase in monocyte counts. The major CTX induced by PHA in mononuclear cells of healthy donors and of IFN‐treated HCL patients was identified as tumor necrosis factor‐α.

Budd-Chiari syndrome in Israel: predisposing factors, prognosis, and early identification of high-risk patients.

In twenty-seven patients with venography-documented Budd-Chiari syndrome (BCS), underlying diseases included polycythemia vera (nine patients), membranous occlusion of the inferior vena cava (three), and cirrhosis (two). In only nine patients did the syndrome occur in the absence of any predisposing factor. All patients with a membranous web were relatively young (mean age 29 years) and were born in Morocco. With regard to prognosis, three groups could be delineated. Eight patients formed a rapidly progressive group, with mean survival from first symptom of only 4.3 weeks, and were characterized mainly by their relatively advanced age and minimal enlargement of the spleen.