Sex hormones and lipoprotein(a) concentration.

INTRODUCTION: increased level of lipoprotein(a) (Lp(a)) constitutes an emerging, independent risk factor for coronary artery disease. Recently, it has been recommended to lower increased (> 50 mg/dl) Lp(a) concentration. Most lipid lowering agents - except niacin - have little or no effect whereas sex hormones significantly reduce Lp(a) level. The effect of sex hormones on Lp(a) level is related to the setting, the drug, the dose and the way of administration. Androgen esters, oral estrogens, alone or in combination with progestogens, and tibolone constantly decrease Lp(a) level, especially in postmenopausal women. AREAS COVERED: this paper reviews the pathophysiology, structure and metabolism of Lp(a). Clinical studies evaluating, in various settings, the effect of exogenous administration of androgens, estrogens - alone or in combination with progestogens - selective receptor estrogen modulators (SERMs), aromatase inhibitors (AIs) and tibolone on Lp(a) level are analyzed. EXPERT OPINION: the results obtained for SERMs are conflicting whereas AIs do not seem to reduce Lp(a) concentration. The effect of hormonal therapy on lipids is complex, depending on drugs and way of administration. Moreover, both androgens and estrogen could determine, in specific settings, severe adverse effects. These drugs are not currently recommended either for treatment of dyslipidemias with increased Lp(a) level or for the prevention of cardiovascular disease.

Sumatriptan therapy for headache and acute myocardial infarction.

IMPORTANCE OF THE FIELD: Migraine is a common, debilitating, chronic neurovascular disorder. Triptans are considered the drugs of choice to treat migraine attacks; however, their use is limited owing to concerns about cardiovascular safety. AREAS COVERED IN THIS REVIEW: The aim of this review is to describe: the mechanisms of action of triptans; the case-reports of acute myocardial infarction (AMI) associated with sumatriptan use; and the results of studies evaluating its tolerability and safety. WHAT THE READER WILL GAIN: Sumatriptan administration can be followed, in close temporal relationship, by AMI in young or adult migraine patients. Some of these cases have developed in subjects taking their first dose. Based on the results of prospective studies, the risk of severe cardiovascular adverse events after the use of a triptan is estimated at 1:100,000 treated attacks. These adverse events, albeit very infrequent, highlight the importance of careful adherence to the sumatriptan prescribing information. TAKE HOME MESSAGE: Inherent in its mechanism of action, sumatriptan could produce (coronary) vasospasm sometimes followed by AMI. The drug should not be prescribed to patients with history, symptoms or signs of ischemic vascular disease; an in-depth evaluation should be carried out in subjects at intermediate cardiovascular risk.

Leukocyte count in peripheral arterial disease: A simple, reliable, inexpensive approach to cardiovascular risk prediction.

BACKGROUND: An elevated leukocyte count is widely proven to predict cardiovascular risk in healthy subjects and coronary patients, but its prognostic role in peripheral arterial disease (PAD) has received scarce attention. OBJECTIVES: To assess the impact of leukocyte count on the incidence of major cardiovascular events in PAD, and verify whether it adds to the prognostic power of the ankle/brachial index (ABI). METHODS: The occurrence of myocardial infarction and stroke was prospectively assessed in 259 consecutive PAD patients. Receiver-operating characteristic analysis and the bootstrap approach were used to identify the best cut-offs to predict the outcome, and hazard ratios (HRs) and c-statistics to assess the ability to classify risk. RESULTS: During a median follow-up of 30.0 months, 28 patients had an event. Adjusted Cox analyses performed on total and differential leukocyte counts, showed that only total leukocyte count (TLC) and neutrophil count (NC), considered as continuous variables, were associated with increased cardiovascular risk (HR=1.35, p<0.01 and HR=1.31, p<0.02, respectively). Patients with ABI < or = 0.63 plus TLC>7.7 x10(9)/L or NC>4.6 x 10(9)/L had a higher risk of about 5-fold vs patients with ABI>0.63 plus TLC< or =7.7 x 10(9)/L (p<0.01) or NC < or = 4.6 x 10(9)/L (p<0.01). The c-statistic for ABI was 0.61, similar to those for TLC (0.63) and NC (0.66). However, it significantly increased to 0.70 and 0.69 for the models incorporating ABI and TLC or ABI and NC, respectively (p<0.05 for both vs ABI alone). CONCLUSIONS: TLC and NC, which are inexpensive and reliable tests, predict major cardiovascular events in PAD, and add to the prognostic power of ABI, currently the most powerful prognostic indicator in these patients.

Prevalence of hypoechoic carotid plaques in coronary artery disease: relationship with coexistent peripheral arterial disease and leukocyte number.

In coronary artery disease (CAD), a concomitant peripheral arterial disease (PAD) entails a more severe coronary atherosclerosis. We hypothesized that the severity of carotid artery disease is greater in CAD+PAD than in CAD alone. In 90 CAD and 79 CAD+PAD patients, carotid plaque echolucency was measured by gray-scale median (GSM), and the degree of carotid stenosis by routine Doppler criteria. Plaques were absent in 20 (22.2%) CAD and 8 (10.1%) CAD+PAD patients (p=0.035), while the prevalence of carotid stenosis>or=50% was 16.7% and 25.3%, respectively (p=0.166). The GSM score was 45.1 [21.7-67.7] in CAD+PAD vs 60.1 [44.9-83.1] in CAD alone (p<0.001). Consistently, hypoechoic plaques (GSM<25th percentile) were more common in CAD+PAD than in CAD patients (38.0% vs 11.4%, p<0.001). On multivariate analysis, CAD+PAD was the only variable significantly associated with hypoechoic plaques (OR=4.16, 95% CI 1.68-10.28). However, when the leukocyte count was added to the model, it showed the strongest association with hypoechoic plaques (OR=6.70, 95% CI 2.13-21.10). In conclusion, compared with CAD alone patients, those with concomitant PAD showed a greater prevalence of plaques with characteristics of instability. Thus, our data suggest that in CAD+PAD, evaluation of carotid plaque echogenicity could contribute to improve clinical decision-making and differentiate treatments for individual patients.

Echolucent femoral plaques entail higher risk of echolucent carotid plaques and a more severe inflammatory profile in peripheral arterial disease.

OBJECTIVE: Plaque instability is recognized as a multivessel phenomenon related to inflammation. This study examined if the morphology of femoral plaques was related to that of carotid plaques. METHODS: The echogenicity of femoral and carotid plaques of 102 patients with peripheral artery disease (PAD) was studied and classified as echolucent or echorich according to the gray-scale median (GSM) value, which was 53.6 for femoral plaques and 55.2 for carotid plaques. Serum C-reactive protein (CRP) levels and neutrophil count were also measured. RESULTS: Echolucent carotid plaques were more frequent in patients with echolucent than in those with echorich femoral plaques (55.8% vs 32.0%; P < .01). At multivariate analysis, femoral GSM lower than the median was the only significant predictor of echolucent carotid plaques (odds ratio [OR], 3.87; 95% confidence interval [CI], 1.53-9.83). Patients with echolucent femoral plaques had higher serum CRP levels (P < .01) and a higher neutrophil count (P = .029) than patients with echorich femoral plaques. However, univariate analysis showed that neutrophil count (OR, 3.48; 95% CI, 1.23-9.85) but not hs-CRP was associated with echolucent carotid plaques. At multivariate analysis, neutrophil count exceeding the median remained associated with echolucent carotid plaques (OR, 5.71; 95% CI, 1.37-23.85), whereas the association between femoral and carotid echolucency was attenuated (OR, 3.75; 95% CI, 0.98-4.43). CONCLUSIONS: In PAD, the presence of echolucent femoral plaques is associated with a greater prevalence of echolucent carotid plaques, probably as a consequence of a more pronounced inflammatory profile. This confirms and extends the finding that plaque echolucency is a multivessel phenomenon. Prospective studies are needed to assess whether carotid screening in PAD patients might contribute to improving clinical decision-making.

Omega-3 polyunsaturated fatty acid in peripheral arterial disease: effect on lipid pattern, disease severity, inflammation profile, and endothelial function.

BACKGROUND & AIMS: Peripheral arterial disease (PAD) is strongly associated with endothelial dysfunction and inflammation, which portend a high cardiovascular risk. Accordingly, we investigated the effects of omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation on endothelial function and inflammatory status in affected individuals. METHODS: PAD patients were randomly divided into two groups. In Group I (n=16) pre-enrollment therapy was not modified, while in Group II (n=16) n-3 PUFAs 1 g b.i.d. for 3 months were added to the previous treatment. Endothelial function was assessed by measuring plasma soluble thrombomodulin (sTM) and brachial artery flow-mediated dilation (FMD), and the inflammatory status by measuring high-sensitivity C-reactive protein and myeloperoxidase. RESULTS: In Group II, n-3 PUFAs reduced sTM levels from the median value of 33.0 ng/mL (interquartile range 16.7, 37.2) to 17.0 ng/mL (11.2, 33.7) (p=0.04), and improved FMD from 6.7% (3.7, 8.7) to 10.0% (6.2, 14.2) (p=0.02). Conversely, these markers did not change in Group I. After 3 months, the levels of inflammatory markers remained unmodified in both groups. CONCLUSIONS: In PAD, n-3 PUFAs induced a marked improvement in endothelial function. Conversely, they did not affect the inflammatory status. In future, large, prospective studies are needed to investigate whether n-3 PUFAs, by improving endothelial function, would reduce the incidence of ischemic events in a population at high risk.

The prevalence of hypoechoic carotid plaques is greater in peripheral than in coronary artery disease and is related to the neutrophil count.

OBJECTIVE: Previous reports indicate that the prevalence and severity of carotid stenoses is greater in peripheral artery disease (PAD) than in coronary artery disease (CAD). To date, no study has compared these two populations with respect to plaque echogenicity, which is an independent risk factor for cerebrovascular events. METHODS: In 43 PAD patients without CAD and in 43 CAD patients without PAD, carotid plaques were studied with high-resolution B-mode ultrasound and by computerized measurement of the gray-scale median. RESULTS: At visual analysis, the prevalence of hypoechoic plaques was 39.5% in PAD and 18.6% in CAD (P = .033). The corresponding values for gray-scale median analysis were 34.9% and 14.0% (P = .024). At multivariate analysis, PAD patients showed a greater risk of having hypoechoic plaques than CAD patients at visual (odds ratio [OR], 4.39, 95% confidence interval [CI] 1.21-15.92, P = .025) and gray-scale median analysis (OR, 5.13; 95% CI, 1.27-20.67; P = .021). This association was no longer significant when neutrophil number was included among the covariates. In this model, only an increased neutrophil count was associated with hypoechoic plaques (P < .01 for both visual and gray-scale median analysis). Indeed, neutrophil count was greater in PAD than in CAD (4.4 +/- 1.0 vs 3.9 +/- 1.2 10(9)/L, P = .030). The concordance between visual typing of carotid plaques and gray-scale median measurement was good (rho = 0.714, P < .01). CONCLUSIONS: Compared with CAD patients, those with PAD, in addition to a greater atherosclerotic burden, may have characteristics of instability of carotid plaques that, in turn, may result in cerebrovascular events. Prospective studies are needed to assess specifically whether the greater prevalence of hypoechoic plaques in PAD vs CAD patients is associated with a greater risk of cerebrovascular events.

Peripheral arterial disease and cardiovascular risk in Italy. Results of the Peripheral Arteriopathy and Cardiovascular Events (PACE) study.

OBJECTIVE: Our knowledge about the natural history of peripheral arterial disease (PAD) is derived from studies carried out almost exclusively in northern European and northern American populations. This study was aimed at defining mortality and cardiovascular morbidity of PAD patients in Italy. METHODS: From the lists of seven general practitioners, we identified all subjects aged 40-80 years (n = 4352). Of those reporting leg symptoms while walking at the Rose Questionnaire (n = 760), 60 (1.6% of the general population) had PAD, as evidenced by an ankle-brachial index of < 0.90 or reduced Doppler flow velocity. For each PAD patient, three sex and age-matched controls negative to the Rose Questionnaire were randomly selected from the general practice lists. RESULTS: After 24 months of follow-up, 15% of PAD patients died, 8% from cardiovascular disease, and 25% developed a non-fatal cardiovascular event. At Cox analysis, the presence of PAD was associated with an increased risk of all-cause mortality (relative risk 4.03; 95% confidence interval 1.50-10.84; P = 0.006), cardiovascular mortality (relative risk 7.77; 95% confidence interval 1.51-40.16; P = 0.014), and non-fatal cardiovascular events (relative risk 3.11; 95% confidence interval 1.41-6.80; P = 0.005). CONCLUSIONS: This Italian study shows that, in general practice, symptomatic PAD is associated with a four-fold increased risk of mortality and a nearly eight-fold increased risk of cardiovascular mortality. These figures are quite similar to those reported in northern European and northern American populations. General practitioners, who are the clinicians primarily and largely responsible for the care of these patients, should be alerted to the consequences of PAD.