Effect of estrogen receptor modulator tamoxifen on blood pressure,plasma renin activity,and renal sodium excretion

BACKGROUND: Adjuvant treatment with the estrogen receptor modulator tamoxifen is a well established long-term therapy in breast cancer. This study investigated the effect of tamoxifen on blood pressure (BP) and on factors by which it might be influenced. METHODS: Normotensive postmenopausal women on > 12 months adjuvant tamoxifen therapy were randomized to withdraw or continue tamoxifen for 6 weeks and then to crossover to the alternative regimen for a second 6-week period. Measurements of clinic and ambulatory BP, plasma renin activity (PRA), and fractional sodium excretion (FE(Na)) were performed at baseline and at the end of each study period. RESULTS: Twenty-three women completed the study (mean age 60.6 +/- 8.3 years). There was no effect of tamoxifen on clinic BP (mean difference between withdrawal and continuation for systolic BP, 0.4 +/- 8.4 mm Hg, 95% confidence interval [CI] -4.0 to 3.2, and diastolic 0.6 +/- 4.7, 95%CI -1.4 to 2.7) or 24-hour ambulatory BP (systolic 0.7 +/- 7.4 mmHg, 95%CI -2.6 to 3.9; diastolic BP, 1.9 +/- 5.5, 95% CI -0.5 to 4.2). Furthermore, no effect of tamoxifen on PRA (mean difference between withdrawal and continuation 0.03 +/- 0.5 ng/mL/h, 95% CI -0.3 to 0.2) or FENa (0.05 +/- 0.5, 95% CI -0.2 to 0.2) was detected. CONCLUSIONS: Tamoxifen seems to have no effect on BP, PRA, or FE(Na) in normotensive postmenopausal women.     

Comparison of circulating proinflammatory cytokines and soluble apoptosis mediators in patients with chronic heart failure with versus without symptoms of depression

This clinical study compared the expression of circulating proinflammatory (tumor necrosis factor-alpha [TNF-alpha] and interleukin-6) and anti-inflammatory (interleukin-10) cytokines and soluble apoptosis mediators (Fas/Fas ligand) between patients with stable chronic heart failure and depressive symptoms (as estimated by the Zung Self-Rating Depression Scale) (n = 15) and those without these symptoms (n = 20). Patients with depressive symptoms exhibited significantly higher levels of TNF-alpha and soluble Fas ligand, as well as significantly lower levels of interleukin-10, than patients without emotional distress. A disregulated cytokine network and activated apoptosis signaling molecules may be actively implicated in the pathophysiology of chronic emotional distress and depressive symptoms in patients with heart failure.     

Growth hormone administration reduces circulating proinflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with chronic heart failure secondary to idiopathic dilated cardiomyopathy

Background Recent studies have shown that an abnormal proinflammatory cytokine expression and apoptotic process contribute to adverse left ventricular remodeling and progress of chronic heart failure. This study investigates the effects of growth hormone (GH) administration on serum levels of representative proinflammatory cytokines and soluble apoptosis mediators in patients with chronic heart failure secondary to idiopathic dilated cardiomyopathy (IDC). Methods Serum levels of tumor necrosis factor-α (TNF-α), its soluble receptors (sTNF-RI, sTNF-RII), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), soluble Fas (sFas) and soluble Fas Ligand (sFasL) were determined (enzyme-linked immunosorbent assay method) in 10 patients with IDC (New York Heart Association class III, ejection fraction 24% ± 2%) before and after a 3-month subcutaneous administration of 4 IU GH every other day (randomized crossover design). Peak oxygen consumption (Vo₂max) was also used to evaluate the functional status of patients with IDC. Results Treatment with GH produced a significant reduction in serum levels of TNF-α (8.2 ± 1.2 vs 5.7 ± 1.1 pg/mL, P < .05), sTNF-RI (3.9 ± 0.4 vs 3.2 ± 0.3 ng/mL, P < .05), sTNF-RII (2.6 ± 0.3 vs 2.2 ± 0.2 ng/mL, P < .05), IL-6 (5.5 ± 0.6 vs 4.4 ± 0.4 pg/mL, P = .05), sIL-6R (32.7 ± 3.0 vs 28.2 ± 3.0 ng/mL, P < .05), sFas (4.4 ± 0.8 vs 3.1 ± 0.6 ng/mL, P < .05), and sFasL (34.2 ± 11.7 vs 18.8 ± 7.3 pg/mL, P < .01). A significant improvement was also observed in Vo₂max after the completion of 3 months' treatment with GH (15.0 ± 0.8 vs 17.2 ± 1.0 mL/kg/min, P < .05). Good correlations were found between GH-induced reduction in TNF-α levels and increase in Vo₂max (r = −0.64, P < .05) as well as between GH-induced reduction in sFasL and increase in Vo₂max (r = −0.56, P = .08). Conclusions GH administration reduces serum levels of proinflammatory cytokines and soluble Fas/FasL system in patients with IDC. These immunomodulatory effects may be associated with improvement in clinical performance and exercise capacity of patients with IDC. (Am Heart J 2002;144:359-64.)     

Depressed Heart Rate Variability as an Independent Predictor of Death in Chronic Congestive Heart Failure Secondary to Ischemic or Idiopathic Dilated Cardiomyopathy

After acute myocardial infarction, depressed heart rate variability (HRV) has been proven to be a powerful independent predictor of a poor outcome. Although patients with chronic congestive heart failure (CHF) have also markedly impaired HRV, the prognostic value of HRV analysis in these patients remains unknown. The aim of this study was to investigate whether HRV parameters could predict survival in 102 consecutive patients with moderate to severe CHF (90 men, mean age 58 years, New York Heart Association [NYHA] class II to IV, CHF due to idiopathic dilated cardiomyopathy in 24 patients and ischemic heart disease in 78 patients, ejection fraction [EF], 26%; peak oxygen consumption, 16.9 ml/kg/min) after exclusion of patients in atrial fibrilation with diabetes or with chronic renal failure. In the prognostic analysis (Cox proportional-hazards model, Kaplan-Meier survival analysis), the following factors were investigated: age, CHF etiology, NYHA class, EF, peak oxygen consumption, presence of ventricular tachycardia on Holter monitoring, and HRV measures derived from 24-hour electrocardiography monitoring, calculated in the time (standard deviation of all normal RR intervals [SDNN], standard deviation of 5-minute RR intervals [SDANN], mean of all 5-minute standard deviations of RR intervals [SD], root-mean-square of difference of successive RR intervals [rMSSD], and percentage of adjacent RR intervals >50 ms different [pNN50]) and frequency domain (total power [TP], power within low-frequency band [LF], and power within high-frequency band [HF]). During follow-up of 584 ± 405 days (365 days in all who survived), 19 patients (19%) died (mean time to death: 307 ± 315 days, range 3 to 989). Cox's univariate analysis identified the following factors to be predictors of death: NYHA (p = 0.003), peak oxygen consumption (p = 0.01), EF (p = 0.02), ventricular tachycardia on Holter monitoring (p = 0.05), and among HRV measures: SDNN (p = 0.004), SDANN (p = 0.003), SD (p = 0.02), and LF (p = 0.003). In multivariate analysis, HRV parameters (SDNN, SDANN, LF) were found to predict survival independently of NYHA functional class, EF, peak oxygen consumption, and ventricular tachycardia on Holter monitoring. The Kaplan-Meier survival curves revealed SDNN <100 ms to be a useful risk factor; 1-year survival in patients with SDNN <100 ms was 78% when compared with 95% in those with SDNN >100 ms (p = 0.008). The coexistence of SDNN <100 ms and a peak oxygen consumption <14 ml/kg/min allowed identification of a group of 18 patients with a particularly poor prognosis (1-year survival 63% vs 94% in the remaining patients, p <0.001). We conclude that depressed HRV on 24-hour ambulatory electrocardiography monitoring is an independent risk factor for a poor prognosis in patients with CHF. Whether analysis of HRV could be recommended in the risk stratification for better management of patients with CHF needs further investigation.

In 102 consecutive patients with stable chronic congestive heart failure and sinus rhythm, several heart rate variability measures derived from 24-hour electrocardiographic recording were significant prognostic risk markers, independent of clinical variables (New York Heart Association class, peak oxygen consumption, left ventricular ejection fraction). The coexistence of the standard deviation of all normal RR intervals <100 ms and peak oxygen consumption <14 ml/kg/min had the worst prognosis, and it is concluded that heart rate variability analysis is useful for noninvasive heart transplant assessment.     

A comparative ultrastructural and molecular biological study on <Emphasis Type="Italic">Chlamydia psittaci</Emphasis> infection in alpha-1 antitrypsin deficiency and non-alpha-1 antitrypsin deficiency emphysema versus lung tissue of patients with hamartochondroma

Background  

Chlamydiales are familiar causes of acute and chronic infections in humans and animals. Human pulmonary emphysema is a component of chronic obstructive pulmonary disease (COPD) and a condition in which chronic inflammation manifested as bronchiolitis and intra-alveolar accumulation of macrophages is common. It is generally presumed to be of infectious origin. Previous investigations based on serology and immunohistochemistry indicated Chlamydophila pneumoniae infection in cases of COPD. Furthermore, immunofluorescence with genus-specific antibodies and electron microscopy suggested involvement of chlamydial infection in most cases of pulmonary emphysema, but these findings could not be verified by PCR. Therefore, we examined the possibility of other chlamydial species being present in these patients.     

Comparison of the smoothness index,the trough : peak ratio and the morning : evening ratio in assessing the features of the antihypertensive drug effect

OBJECTIVE: To provide a direct comparison of the trough : peak ratio (TPR), the morning : evening home blood pressure ratio (MER) and the smoothness index (SI) in assessing the features of the antihypertensive drug effect. PATIENTS AND METHODS: A total of 27 untreated hypertensives were randomized to receive lisinopril 20 mg o.d. or losartan 50 mg o.d. for 5 weeks and were subsequently crossed-over to the alternative treatment for a second 5-week period. Twenty-four hour ambulatory and 5-day home blood pressure were monitored before randomization and at the end of each treatment period. TPR, MER and SI were calculated for each drug for the total study population and for responders only. RESULTS: When all patients were considered, lisinopril provided higher values of TPR [0.63/0.66 for systolic/diastolic blood pressure (SBP/DBP)], MER (1.02/0.77) and SI (1.01/0.87) than losartan (0.35/0.51, 0.60/0.60 and 0.64/0.53, respectively). Analysis of responders only, again showed a clear advantage of lisinopril over losartan in TPR (0.77/0.67 versus 0.44/0.47, respectively) and MER (0.86/0.87 versus 0.48/0.61), whereas there was no difference in SI (1.25/1.13 for lisinopril versus 1.11/1.12 for losartan). CONCLUSIONS: These data suggest that the assessment of the duration of the antihypertensive drug effect provided by the MER is consistent to that by the TPR and that two drugs with different levels of TPR and MER may have the same level of SI. It appears that the SI is not simply a more reliable index of the features of the antihypertensive drug effect, but offers a different type of information complementary to that provided by the TPR and the MER, in regard to the homogeneity and the magnitude but not the duration of the antihypertensive effect.     

Effects of growth hormone on circulating cytokine network, and left ventricular contractile performance and geometry in patients with idiopathic dilated cardiomyopathy.

BACKGROUND: Recent experimental and clinical data indicate that abnormal central and peripheral immune reactions contribute to the progression of chronic heart failure, and that immunomodulation may be an important therapeutic approach in this syndrome.Aims We sought to study the effects of growth hormone (GH) administration on circulating pro-inflammatory/anti-inflammatory cytokine balance, and to investigate whether these GH-induced immunomodulatory effects are associated with the improvement of left ventricular (LV) contractile performance in idiopathic dilated cardiomyopathy (DCM) patients. METHODS: Plasma pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF) and its soluble receptor (sGM-CSFR), chemotactic cytokine macrophage chemoattractant protein-1 (MCP-1), soluble adhesion molecules intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1), and, finally, anti-inflammatory cytokines interleukin-10 (IL-10) and transforming growth factor-beta2 (TGF-beta2) were measured (ELISA method) in 12 patients with DCM (NYHA class III; LV ejection fraction: 23.6+/-1.7%) before and after a 3-month subcutaneous administration of GH 4IU every other day (randomized crossover design). Peak oxygen uptake (VO2 max), LV dimensions, LV mass index, end-systolic wall stress (ESWS), mean velocity of circumferential fibre shortening (Vcfc), and contractile reserve (change of ratio Vcfc/ESWS after dobutamine administration) were also determined at the same period. RESULTS: Treatment with GH produced a significant reduction in plasma TNF-alpha (7.8+/-1.1 vs 5.5+/-0.9pg/ml, P=0.013), IL-6 (5.7+/-0.5 vs 4.7+/-0.4pg/ml, P=0.043), GM-CSF (27.3+/-1.7 vs 23.3+/-1.8pg/ml, P=0.042), sGM-CSFR (4.0+/-0.4 vs 3.2+/-0.4ng/ml, P=0.039), MCP-1 (199+/-5 vs 184+/-6pg/ml, P=0.048), sICAM-1 (324+/-34 vs 274+/-27ng/ml, P=0.008) and sVCAM-1 (1238+/-89 vs 1043+/-77ng/ml, P=0.002) in DCM patients. A significant increase in ratios IL-10/TNF-alpha (1.9+/-0.3 vs 3.5+/-0.9, P=0.049), IL-10/IL-6(2.6+/-0.6 vs 3.2+/-0.5, P=0.044) and TGF-beta2/TNF-alpha (3.1+/-0.6 vs 4.4+/-0.6, P=0.05) was alsofound with GH therapy. A significant reduction in ESWS (841+/-62 vs 634+/-48gr/cm(2), P=0.0026) and LV end-systolic volume index (LVESVI, 128+/-12 vs 102+/-12ml, P=0.035) as well as a significant increase in posterior wall thickness (PWTH, 9.2+/-0.5 vs 10.3+/-0.6mm, P=0.034), contractile reserve (0.00029+/-0.0001 vs 0.00054+/-0.0001circ*cm(2)/gr*s, P=0.00028) and VO2max (15.3+/-0.7 vs 17.1+/-0.9ml/kg/min, P=0.002) were observed after GH administration. Good correlations were found between GH-induced increase in contractile reserve and the increases in VO2max (r=0.63, P=0.028), IL-10/TNF-alpha (r=0.69, P=0.011) and TGF-beta2/TNF-alpha (r=0.58, P=0.046) ratios, as well as the reduction in plasma TNF-alpha levels (r=-0.86, P=0.0004). CONCLUSIONS: GH administration modulates beneficially circulating cytokine network and soluble adhesion molecules in patients with DCM, whilst enhancing contractile reserve and diminishing LV volumes. These GH-induced anti-inflammatory effects may be associated with the improvement in LV contractile performance and exercise capacity as well as with the reverse of LV remodelling of patients with DCM.     

Lungenresektionen

The physician involved in internal medicine and general practice is confronted with a series of challenges in patients with pulmonary resection. In the early post-operative phase, optimal analgesia and physiotherapy are the primary factors for achieving the best possible function after loss of pulmonary tissue and for the determination of complications. Post thoracotomy syndrome requires interdisciplinary therapy. In the later course, it is necessary to take into consideration effects on pulmonary circulation, on the musculoskeletal system and on the digestive tract as well as sleep disturbances due to diaphragm dysfunction. Corresponding symptoms should be considered and actively sought, for example using echocardiography for assessment of cor pulmonale or outpatient sleep monitoring for detection of sleep-disordered breathing. Thus, aftercare includes much more than the search for a relapse or formation of metastases in cases of the most common cause of pulmonary resection, bronchial cancer.     

Risks of neoadjuvant chemotherapy and radiation therapy

Pulmonary resection for locally advanced NSCLC after induction chemotherapy or chemoradiotherapy can generally be performed with acceptable morbidity and mortality. Data from several phase II and a few randomized trials showed that patients should be carefully selected for surgery especially with respect to their age, performance status, and pulmonary and cardiovascular function tests. The presence of cardiovascular disease should be actively investigated and preexisting arrhythmias appropriately managed. Similarly, respiratory status should be evaluated and any reversible condition, such bronchial obstruction, infection, pulmonary embolism, and smoking, should be addressed. Surgical resection is technically more demanding; intraoperative blood loss should be minimized. Several studies demonstrated that pneumonectomy especially on the right side is associated with a significantly increased risk of postoperative morbidity and mortality especially in patients after induction chemoradiotherapy. Therefore, pneumonectomy should be performed very selectively and only when alternative procedures such as bronchial or vascular sleeve resection or both are technically not possible. Long-term follow-up reports of bimodality protocols without surgery versus bimodality followed by surgical resection are awaited. These results will heln to define standards of care and the role of surgery for patients with NSCLC stage III disease. Future decision-making will have to take into account treatment morbidity and mortality and parameters of organ-sparing surgery following induction. probably best represented by rates of pneumonectomy or rates of lobectomy in different patient groups.