Antonello Silvestri

Increased Levels of C-Reactive Protein After Oral Hormone Replacement Therapy May Not Be Related to an Increased Inflammatory Response

Background—It has been suggested that hormone replacement therapy (HRT) in postmenopausal women is associated with an increased inflammatory response that may trigger acute cardiovascular events. This suggestion is mainly based on the finding of elevated C-reactive protein (CRP) levels after HRT. The aim of the present study was to evaluate a broad spectrum of vascular inflammation markers in 389 postmenopausal women with increased cardiovascular risk at baseline and after either 6 months of HRT (126 women) or no HRT (263 women). Methods and Results—Compared with baseline, CRP levels significantly increased after HRT (0.9±0.2 versus 1.6±0.4 mg/L, P <0.01); on the contrary, soluble intracellular adhesion molecule-1 decreased from 208±57 to 168±37 ng/mL (P <0.01) after HRT. Similarly, vascular cell adhesion molecule-1 decreased from 298±73 to 258±47 ng/mL (P <0.01), plasma E-selectin levels were reduced from 17.8±5.6 to 14.8±3.9 ng/mL (P <0.01), interleukin-6 levels decreased from 1.51±0.22 to 1.29±0.28 pg/mL, and s-thrombomodulin plasma levels decreased from 4.8±0.7 to 4.3±0.9 ng/mL (P <0.01). No significant changes in either CRP or vascular inflammatory marker were detected in women not taking HRT. Conclusions—The discrepancy between increased plasma levels of CRP and reduced plasma levels of all other markers of inflammation suggests that the increased CRP levels after oral HRT may be related to metabolic hepatic activation and not to an acute-phase response. HRT seems to be associated with an overall decrease in vascular inflammation.

Hormone Replacement Therapy and Cardioprotection

Abstract: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in women after the age of 50 years in most developed countries. Estrogen deficiency plays a key role in causing CVD in women. Apart from the direct effect of ovarian hormones on the vessel wall, cessation of ovarian function and the consequent reduction of sex steroid hormone levels have important metabolic and pathological implications that negatively influence the cardiovascular system. Therefore, the increased incidence of CVD observed in women after menopause should be considered on a multifactorial basis. Data available for the effects of ERT and HRT in the primary prevention of CVD are mainly observational. However, despite limitations related to this kind of study, it must be noted that their results consistently show a reduction in cardiovascular events in hormone users. Meta‐analysis of epidemiological studies found that women who had ever used estrogens had a 34% overall reduction in the relatrive risk of cardiovascular events compared to those who had never used hormones. Most of the early epidemiological studies were conducted using unopposed estrogen replacement therapy. The number of studies evaluating the effects of estrogen‐progestin replacement therapy is limited. Recently, the estrogen‐progestin arm of the Womens Health Initiative (WHI) study has been stopped because of an increased incidence of breast cancer, and too early on to give any insight into possible cardiovascular effects. Comments on the cardiovascular effects of HRT from the results of the WHI study are therefore not warranted, as the study did not continue for a duration long enough to enable a calculation of cardiovascular end points. The WHI study included only one single type of estrogen‐progestin association; whether different estrogen‐progestin combinations, more commonly used outside the United States, may have a different effect is still a matter of speculation. A major difference between observational and randomized studies on the effect of ovarian hormones on cardiovascular function is the time of HRT initiation since menopause, which is significantly shorter in obersvational studies. In conclusion, the average 35–50% risk reduction in CVD with HRT in primary prevention in postmenopausal women is based on nonrandomized observational data.

Interleukin-6 and flow-mediated dilatation as markers of increased vascular inflammation in women receiving hormone therapy.

Objective: The lack of a beneficial long-term cardiovascular effect of hormone therapy and the early incidence of cardiovascular adverse events observed in recent randomized studies have been related to a heightened inflammatory effect of hormone therapy. Design: We evaluated the effect of different postmenopause therapies on inflammatory markers and endothelial function in 205 postmenopausal women before and after therapy. Results: In all postmenopausal women, estrogens alone increased plasma levels of C-reactive protein (CRP) but decreased all other markers of inflammation including interleukin-6 (IL-6) (CRP: +75% ± 11%, intracellular adhesion molecule: −21% ± 4%, vascular cell adhesion molecule: −15% ± 6%, E-selectin: −18% ± 4%, s-thrombomodulin −10.5% ± 3.7%, IL-6 −14% ± 6%; percent changes, P < 0.01 compared with baseline). Raloxifene and tibolone did not significantly affect the overall inflammatory milieu. In a minority of patients, estrogen-progestogen associations and tibolone increased IL-6 levels and induced unfavorable changes on inflammation markers (CRP: +93% ± 8%, intracellular adhesion molecule: −3% ± 2%, vascular cell adhesion molecule: −5% ± 2%, E-selectin: +6% ± 2%, s-thrombomodulin: +5% ± 2%, IL-6: +12% ± 4%; percent changes compared with baseline). Patients with increased IL-6 levels were older and had a longer time since menopause. In all patients except those with increased IL-6 levels, hormone therapy improved endothelial function, whereas tibolone and raloxifene did not significantly change endothelial function compared with baseline. A worsening of endothelial function was detected in patients with increased IL-6 levels during therapy. Conclusions: Postmenopausal hormone therapy is associated with decreased vascular inflammation; however, in patients with a longer time since menopause, postmenopause hormone therapy may increase inflammation and worsen endothelial function. These unfavorable vascular effects may be detected by an elevation in IL-6 levels and by a lack of improvement in endothelial function.

Dydrogesterone does not reverse the effects of estradiol on endothelium-dependant vasodilation in postmenopausal women: a randomised clinical trial

OBJECTIVES The purpose of this study was to evaluate endothelium-dependent flow-mediated dilation (FMD) in the brachial artery and the plasma levels of endothelin-1 in postmenopausal women at risk for coronary artery disease before and after treatment with both estradiol and estradiol plus dydrogesterone. METHODS Sixteen postmenopausal women (PMW) (mean age 58+/-9 years) with more than two risk factors for coronary artery disease, were randomized to receive either oral estradiol (2 mg) for 28 days or oral estradiol (2 mg) for 14 days and oral estradiol (2 mg) and dydrogesterone (10 mg) for 14 days, in a double-blind, placebo-controlled, single cross-over study. Patients were crossed-over the complementary treatment 7 days after completing the first treatment. The study of forearm blood flow and the measurement of plasma endothelin-1 levels was carried out before and after each treatment. RESULTS Estradiol significantly increased FMD as compared to baseline; the addition of dydrogesterone did not affect the effect of estradiol on FMD. Similarly reactive hyperemic flow increased after estradiol alone or in association with dydrogesterone compared to baseline. Plasma levels of endothelin-1 were significantly reduced by estradiol both when administered alone or in association with dydrogesterone. CONCLUSIONS Hormone replacement therapy with estradiol and dydrogesterone improves endothelial function and reduces plasma levels of endothelin-1 in PMW at risk for coronary artery disease.

What about the combined action of poly‐herbal on wound healing?

To the Editor: We read with great interest the article by Budovsky et al. and appreciated it very much. We agree that chronic wounds are a frequent finding in clinical practice and are one of the problems with high impact on social health, affecting mainly the elderly people with chronic diseases (diabetes, nutritional abnormalities, cardiovascular diseases chronic motor deficit and obesity) which are associated with alterations in wound healing due to skin repair damaged mechanisms. Moreover, while current therapeutic agents have generally inadequate efficacy and number of serious adverse effects, the medicinal plants have been used in medicine since ancient times and are well known for their abilities to promote wound healing and prevent infection without grave side effects. This is why herbal therapy may be an alternative strategy for treatment of wounds. In a recently performed literature review, we found few references that attempted to introduce herbal remedies and their mechanisms of action in healing of skin wounds and also provide useful information for the development of more effective wound repair drugs. The purpose of the review by Budovsky et al. was to collect all the data on each medicinal plant of the world flora with wound healing activity, evaluating the single biologically active substance belonging to different herbal preparations and describing in detail its cellular and molecular mechanism of action in the process of wound healing. Moreover, Bahramsoltani et al. studied the effect of medical plants and their natural components in the treatment of burn wounds. Conversely, in clinical practice are currently available various poly-herbal preparations containing different natural components that have been claimed to be useful in treating wound healing. This mixture of extracts is excluded to be made or used commercially by others before the patent expiration. Because of their different mechanisms of action, many combinations of phytochemicals can interact in a synergistic fashion. One phytochemical may impact the metabolism of the other, or change its ability to enter or leave the cell; therefore, these compositions are only tested in anecdotal papers and there are not randomized controlled trials or systematic reviews. Considering that the literature is poor in this field, we think it would be relevant for readers if Budovsky et al. could express their expert opinion on the following subject: it could be more useful to optimize the management of chronic skin wounds, focus on these various poly-herbal preparation with different active ingredients rather than a single substance?

Rotigotine improves executive functions in patients with vascular dementia

background activity but no interictal discharges suggestive of epilepsy. Neuropsychological evaluations with 2-year intervals showed progressivewordfinding difficulties, attentionand memory-deficits. He became nearly mute and apathetic and was unable to continue his work as a process-controller. The MRI was repeated 8-year after symptom-onset showing prominent atrophy of the left hemisphere (figure), consistent with the clinical diagnosis progressive non-fluent aphasia. Case-management was still lacking at referral to our memory clinic. The presence of epilepsy in the presented patient with PPA has led to a long-lasting delay in clinical diagnosis and adequate care. Patients with subtle speech difficulties usually seek medical attention on average 2-3 years after symptom-onset. Primary and secondary care physicians often do not recognise PPA-symptoms adding a further diagnostic delay. Complaints are often attributed to psychogenic factors (burnout, mood or anxiety) or to other comorbid conditions, which even led to a diagnostic delay of 8 years in our case. Conclusions: An atypical age-at-onset, slow disease progression, absence of cognitive or behavioural problems are all factors delaying referral to a memory clinic in PPA. Diagnostic delay is even more pronounced in the presence of comorbid conditions which may affect speech.

P1-210: Cytokines are not predictive of Alzheimer's disease in patients with mild cognitive impairment

pends on the identification of symptoms by the patient or a family member. However, the relationship between the cognitive complaints made by patients or family members and the clinical diagnosis of either AD or mild cognitive impairment (MCI) remains unclear. Methods: Archival data from 386 patients were extracted from the Boston University Alzheimer’s Disease Center Registry. Participants were diagnosed by a consensus conference as cognitively normal (n 119), MCI (n 163), or AD (n 104). Variables extracted included selfand informant ratings about the presence or absence of impairments in the participant’s memory, judgment, language, visuospatial function, and attention. Crosstabulations were conducted to determine the agreement between participant and informant ratings. Results: For the entire group of participants, substantial discrepancies existed on questions addressing the presence or absence of impairments in memory, judgment, language, visuospatial function, and attention. Participants and their informants disagreed most often on judgment, attention, and visuospatial function; least often on memory; and with an intermediate level of agreement regarding language function. When broken down by diagnostic group, participants with AD and their informants were in agreement 76% of the time regarding the presence of absence of memory symptoms, but only 26% of AD participants agreed with informants who endorsed impaired judgement.Concordance on ratings of language, visuospatial function, and attention were around chance levels. Participants with MCI agreed with their informants 68% of the time with regard to symptoms of memory impairment. There was good agreement in the other domains, primarily due to the fact that few abnormal ratings were made by either the participants or their informants. Interestingly, a greater proportion of participants with MCI (31%) endorsed significant memory symptoms than did their informants (15%). Conclusions: Elderly individuals and their family members often disagree on the presence of absence of cognitive symptoms. Participants with MCI and AD appear to be in better agreement with informants about memory functioning than functioning in other cognitive domains. Awareness of reduced judgment may be particularly lacking in AD.

IC-P2-137: Role of leucocyte count and thyroid-stimulating hormone in evolution of mild cognitive impairment to dementia

Background: Patients with Mild Cognitive Impairment (MCI) have an increased risk of development into dementia. Recently it has become clear that late-onset Alzheimer’s disease (AD) is associated with atherosclerotic disease and that vascular and inflammatory components are important in the development of dementia. In fact, evidences suggest that vascular and inflammatory components may be important in the etiology of dementia, and accumulating evidence indicate that lateonset AD is also associated with atherosclerotic disease. Methods: A total of 36 consecutive patients (76.4 5.3 years old, M/F 18/18) with MCI have been studied and followed with regular clinic visits at 6 months interval during a mean follow up of 18 months. At each visit a full medical and neurological evaluations were performed together with blood tests, electrocardiogram (ECGs), and neuropsychological tests. Results: Over a mean follow up of 18 months 8 out of 36 patients (M/F 7/1)developed dementia. Patients who developed dementia had baseline levels of thyroid stimulating hormone (TSH) and leucocyte count significantly higher than those who did not developed dementia. At the multivariate analysis TSH and leucocyte count resulted as independent predictors of dementia. Conclusions: MCI evolution into dementia is facilitated by subclinical hypothyroidism and by inflammation. Further large scale studies are needed to further clarify these findings.

Metformin improves endothelial function in patients with metabolic syndrome X

BACKGROUND Metabolic Syndrome (MS) is associated with impaired endothelial function and increased cardiovascular risk. Insulin resistance is a key feature of MS and plays an important role in the pathogenesis of endothelial dysfunction. Aim of the present study was to evaluate the effect of metformin on endothelial function and insulin resistance, assessed by the homeostasis model (HOMA-IR, homeostasis model assessment-insulin resistance), in patients with MS. METHODS Sixty-five subjects (37 men and 28 women, mean age 54 +/- 6 years) with MS were allocated to receive metformin 500 mg twice daily (n = 32) or placebo (n = 33) for 3 months. Before and after treatment we assessed endothelial function, using flow-mediated dilatation of the brachial artery, and HOMA-IR. RESULTS Patients who received metformin demonstrated statistically significant improvement in endothelium-dependent vasodilation compared with those treated with placebo (from 7.4 +/- 2.1% to 12.4 +/- 1.9% vs. 7.3 +/- 2.5% to 6.9 +/- 2.7%, P = 0.0016, metformin vs. placebo respectively), without significant effect on endothelium-independent response to sublingual glyceryl trinitrate (P =0.32). Metformin improved insulin resistance compared with placebo group (HOMA-IR from 3.39 to 2.5 vs. 3.42 to 3.37; 26% reduction in HOMA-IR, P = 0.01). An association between the improvement in insulin resistance and the improvement in endothelial function (r = -0.58, P = 0.0016) was found. CONCLUSION Metformin improves both endothelial function and insulin resistance in patients with MS. These findings support the central role of insulin resistance in the development of endothelial dysfunction and the role of metformin for the treatment of patients with MS.

Different effect of hormone replacement therapy, DHEAS, and tibolone on endothelial function in postmenopausal women with increased cardiovascular risk

Menopause is associated with an increased cardiovascular risk and with a decrease in endothelial function. Hormone replacement therapy (HRT) improves endothelial function in post-menopausal women (PMW) without established atherosclerosis. New alternative treatments, among which tibolone (T) and DHEAS have been suggested to reduce postmenopausal cardiovascular risk. Although, in vitro animal studies have suggested that T and DHEAS improve endothelial function, their effect in humans has never been tested. The aim of the present study was to compare the effects of HRT (continuous combined 0.625 mg conjugated equine estrogen plus 2.5 mg/d medoxyprogesterone) DHEAS and T on endothelium-dependent flow-mediated vasodilatation (FMD), plasma nitrite, nitrate and endothelin-1 levels in 16 PMW with increased cardiovascular risk in a double-blinded, double-crossover study. Women were randomized and treated for 4 weeks with HRT, T or DHEAS. Brachial artery diameter, FMD, endothelin-1 and plasma nitrite and nitrate levels were measured at baseline and after each treatment phase. Brachial artery diameters remained unchanged after each treatment phase. HRT significantly improved FMD compared to both baseline and to T and DHEAS therapies while no effect of T or DHEAS on FMD was noted. In conclusion, HRT, but neither T nor DHEAS, improves endothelial function and reduces plasma levels of endothelin-1 in PMW at risk of CAD.