Mišo Šabovič

Influence of atorvastatin treatment on L-arginine cerebrovascular reactivity and flow-mediated dilatation in patients with lacunar infarctions

Background and Purpose— In our study we hypothesized that statins improve endothelial function in patients with lacunar infarctions (LI). Cerebral and systemic endothelial function was determined before and after 3-months treatment with atorvastatin. Methods— Cerebral endothelial function was determined by l-arginine reactivity and systemic endothelial function by flow-mediated dilatation (FMD) in patients with LI (18 patients, aged 61.1±7.6 years), 20 age- and gender-matched patients with similar risk factors (SR) and 19 age- and gender-matched healthy controls. The mean arterial velocity (vm) in both middle cerebral arteries was measured by transcranial Doppler sonography before, during and after a 30-minute intravenous infusion of l-arginine. FMD of the brachial artery after hyperaemia was determined. The measurements were repeated after 3-months treatment with 40 mg of atorvastatin per day. Results— l-arginine reactivity was decreased in LI patients (13.1±8.4%) and in patients with SR compared with healthy controls (P≤0.01). FMD was more impaired in patients with LI (0.06±4.9%) compared with patients with SR and healthy controls (P≤0.01). After atorvastatin treatment, l-arginine reactivity and FMD improved in both patients with LI (17.1±7.6%; 7.0±5.7%) and patients with SR (P≤0.01). Previously mildly increased cholesterol values normalized. Conclusion— The decreased l-arginine reactivity and FMD improve after atorvastatin treatment in both patients with LI and patients with SR.

Arterial Stiffness and Cardiovascular Therapy

The world population is aging and the number of old people is continuously increasing. Arterial structure and function change with age, progressively leading to arterial stiffening. Arterial stiffness is best characterized by measurement of pulse wave velocity (PWV), which is its surrogate marker. It has been shown that PWV could improve cardiovascular event prediction in models that included standard risk factors. Consequently, it might therefore enable better identification of populations at high-risk of cardiovascular morbidity and mortality. The present review is focused on a survey of different pharmacological therapeutic options for decreasing arterial stiffness. The influence of several groups of drugs is described: antihypertensive drugs (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta-blockers, diuretics, and nitrates), statins, peroral antidiabetics, advanced glycation end-products (AGE) cross-link breakers, anti-inflammatory drugs, endothelin-A receptor antagonists, and vasopeptidase inhibitors. All of these have shown some effect in decreasing arterial stiffness. Nevertheless, further studies are needed which should address the influence of arterial stiffness diminishment on major adverse cardiovascular and cerebrovascular events (MACCE).

The effects of low-dose fluvastatin and valsartan combination on arterial function: A randomized clinical trial

BACKGROUND Ageing progressively diminishes arterial functions, even in the absence of traditional risk factors. Our aim was to explore whether age-related arterial changes in middle-aged males could be reversed using short-term, low-dose fluvastatin/valsartan combination intervention. METHODS Forty apparently healthy, middle-aged males (43.3 ± 5.8 years) were recruited in a double-blind, randomised intervention. Individuals received either 10mg fluvastatin/20mg valsartan daily or placebo over 30 days. The brachial artery flow mediated dilation (FMD), pulse wave velocity (PWV) and common carotid artery β-stiffness were assessed at baseline and after 30 days, and again 5-10 months after therapy discontinuation. RESULTS Arterial function variables significantly improved after 30 days of intervention; FMD improved by 167.7% (P<0.001), PWV by 10.9% (P<0.05) and β-stiffness by 18.8% (P<0.01), whereas no changes were obtained in the placebo group. The favourable outcomes in the intervention group were accompanied by a significant decrease of high sensitivity-C reactive protein levels (1.8-fold; P<0.05). In contrast, lipids and blood pressure remained unchanged. Surprisingly, the beneficial arterial effects were still present to a substantial degree 7 months after completing intervention (remaining % of initial improvement: FMD 82.1%, PWV 69.5% and β-stiffness 68.5%), but declined substantially after 10 months. CONCLUSION Our results indicate that age-related arterial changes, at least in middle-aged males, can be reversed. Short-term treatment with a low-dose fluvastatin/valsartan combination resulted in a large and long lasting improvement of arterial function.

Interleukin-6 is a stronger prognostic predictor than high-sensitive C-reactive protein in patients with chronic stable heart failure.

Heart failure is characterized by activation of the immune system which is strongly associated with disease severity and outcome. We sought to compare the prognostic impact of two established inflammatory markers — interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) — in patients with chronic heart failure. In stable, optimally managed outpatients with chronic heart failure, baseline levels of hsCRP and IL-6 were determined. Clinical follow-up was obtained and the rate of events (heart failure related deaths or hospitalizations) were recorded. We included 201 patients (32.7% female, NYHA class II [66.2%] or III [33.8%], mean age 70 years). During a median follow up of 614 (367−761) days, 64 (30.9%) patients experienced an event; those with an event had higher levels of hsCRP (median 2.93 [interquartile range 2.36−8.92] vs 2.23 [1.32−5.77] mmol/l) and IL-6 (7.8 [4.7−10.3] vs 4.3 [2.6−7.9] pg/ml). However, on Cox multivariate analysis, IL-6 but not hsCRP emerged as an independent predictor of prognosis (hazard ratio HRadjusted 2.74, 95% confidence interval 1.17−6.43; P = 0.020). Our findings suggest that IL-6 is a better prognostic predictor than hsCRP in patients with chronic stable heart failure.

Interleukin-6 Correlates with Endothelial Dysfunction in Young Post-Myocardial Infarction Patients

Background: The estimation of coronary risk based on consideration of classical risk factors is insufficient in young patients with myocardial infarction who have low expressions of classical risk factors. Endothelial dysfunction (ED) and markers of vascular inflammation may be more appropriate for risk estimation. The relations among ED and inflammation markers in such patients have not yet been explored. Patients and Methods: Twenty-one patients (on average 44 years old) in the stable phase after myocardial infarction, with low expressions of risk factors, were included in the study. The control group consisted of 25 healthy age-matched males. ED was estimated by ultrasound measurement of the endothelium-dependent dilatation of the brachial artery. The following inflammation markers were measured: hsCRP, interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), ICAM-1, VCAM-1, selectin-P and selectin-E. Results: Patients had a significantly reduced level of endothelium-dependent vasodilatation (5.6 ± 3.5 vs. 8.8 ± 6.5%, p < 0.05), and an increased level of IL-6 (3.2 [1.5–8.4] vs. 1.4 [0.9–2.3] ng/ml; p < 0.01). All other inflammation markers were comparable to controls. We found a significant negative correlation between ED and the levels of IL-6 (r = –0.54, p = 0.012). Conclusion: It appears that IL-6 is the most valuable circulating marker of ED, and consequently a useful marker of coronary risk.

Endothelial dysfunction, intima-media thickness, ankle-brachial pressure index, and pulse pressure in young post-myocardial infarction patients with various expressions of classical risk factors

Coronary risk assessment based on the presence of classical risk factors may be insufficient. Several markers of arterial function and morphology, such as endothelial dysfunction (ED), intima-media thickness (IMT), ankle-brachial pressure index (ABPI), and pulse pressure (PP) may be useful in coronary risk estimation. To investigate their usefulness, we compared them in young post-myocardial infarction (MI) patients with various expressions of classical risk factors. Young male patients (on average 44 years old) in the stable phase after MI were included in the study. Twenty patients had high and 21 patients low expression of risk factors, while 25 healthy age-matched males served as controls. Endothelial dysfunction (estimated by ultrasound measurement of the flow-mediated dilation [FMD] of the brachial artery), IMT (of common carotid arteries), ABPI, and PP were compared between both groups of patients and controls. Compared with the control group, endothelial function and IMT were significantly impaired in both groups of patients, whereas ABPI was significantly reduced only in high-risk patients, and PP was similar in patients and controls. In all subjects, the level of FMD was significantly negatively related to IMT (r = −0.38, P = 0.01). Our study showed that endothelial function and IMT (but not ABPI and PP) are impaired in young post-MI patients independently of presence or absence of classical risk factors. Thus, we conclude that in young patients ED and IMT better assess coronary disease than classical risk factors, and are probably better markers of coronary risk.

Cerebrovascular Reactivity to L- Arginine in Patients with Lacunar Infarctions

Background: It is well known that endothelial dysfunction plays an important role in the pathogenesis of many cardiovascular disorders. The aim of this study was to test the hypothesis that specific, marked endothelial dysfunction of cerebral arteries is present in patients with lacunar cerebral infarctions. Methods: Cerebrovascular reactivity to L-arginine, which reveals the function of the cerebral endothelium, was investigated in patients with lacunar infarctions (20 patients, 11 male and 9 female, aged 60.9 ± 7.3 years), 21 age- and gender-matched asymptomatic patients with similar cardiovascular risk factors (all patients had arterial hypertension) and 21 age- and gender-matched healthy controls. The mean arterial velocity (vm) in both middle cerebral arteries was measured by transcranial Doppler sonography during a 15-min baseline period, a 30-min intravenous infusion of L-arginine and a 15-min interval after L-arginine infusion. Arterial blood pressure, heart rate and CO2 were measured continuously. Results: The measured vm increase during L-arginine infusion in the patients with lacunar infarctions (13.4 ± 9.1%) was significantly lower compared to the healthy controls (20.5 ± 9.9%) but similar to that obtained in the patients with cardiovascular risk factors (11.5 ± 8.9%). Conclusions: Our results showed that cerebrovascular reactivity to L-arginine, which demonstrates cerebral endothelial function, is significantly impaired in patients with cardiovascular risk factors. Importantly, we found that patients with lacunar infarctions do not show any additional impairment of cerebral endothelial function.

Coenzyme Q10 Supplementation Decreases Statin-Related Mild-to-Moderate Muscle Symptoms: A Randomized Clinical Study

Background Statin use is frequently associated with muscle-related symptoms. Coenzyme Q10 supplementation has yielded conflicting results in decreasing statin myopathy. Herein, we tested whether coenzyme Q10 supplementation could decrease statin-associated muscular pain in a specific group of patients with mild-to-moderate muscle symptoms. Material/Methods Fifty patients treated with statins and reporting muscle pain were recruited. The Q10 group (n=25) received coenzyme Q10 supplementation over a period of 30 days (50 mg twice daily), and the control group (n=25) received placebo. The Brief Pain Inventory (BPI) questionnaire was used and blood testing was performed at inclusion in the study and after 30 days of supplementation. Results The intensity of muscle pain, measured as the Pain Severity Score (PSS), in the Q10 group was reduced from 3.9±0.4 to 2.9±0.4 (P<0.001). The Pain Interference Score (PIS) after Q10 supplementation was reduced from 4.0±0.4 to 2.6±0.4 (P<0.001). In the placebo group, PSS and PIS did not change. Coenzyme Q10 supplementation decreased statin-related muscle symptoms in 75% of patients. The relative values of PSS and PIS significantly decreased (−33.1% and −40.3%, respectively) in the Q10 group compared to placebo group (both P<0.05). From baseline, no differences in liver and muscle enzymes or cholesterol values were found. Conclusions The present results show that coenzyme Q10 supplementation (50 mg twice daily) effectively reduced statin-related mild-to-moderate muscular symptoms, causing lower interference of statin-related muscular symptoms with daily activities.

Inflammation markers in patients with coronary artery disease ― comparison of intracoronary and systemic levels

SummaryBACKGROUND AND AIM: Raised levels of inflammation markers are associated with worse prognosis in patients with coronary artery disease. It is generally believed, although it has never been proven, that inflammation markers are released from (un)stable plaques in coronary arteries. We investigated this issue by directly comparing levels of inflammation markers in coronary and systemic blood. PATIENTS AND METHODS: Patients with acute coronary syndrome (N = 11), stable angina pectoris (N = 10) and controls with noncoronary origin of chest pain (N = 9) were included in the study. Intracoronary blood samples were taken at the culprit lesion in the coronary artery in patients with acute coronary syndrome and from any coronary artery in the other two groups, together with systemic blood samples from the femoral vein and artery. Levels of high-sensitivity C reactive protein (hsCRP), interleukin 6, interleukin 8, interleukin 10, soluble receptor for interleukin 2 (tR IL-2) and myeloperoxidase were measured in all samples. RESULTS: We found significantly elevated levels of hsCRP and interleukin 10 in patients with acute coronary syndrome compared with patients with stable angina and the control patients. Notably, we did not find any difference between intracoronary and systemic levels of any inflammatory marker in patients with acute coronary syndrome. Furthermore, no difference between intracoronary and systemic levels of markers was present in patients with stable angina or in the control group. CONCLUSIONS: We observed that excess circulating inflammation markers, being characteristic of unstable coronary artery disease, are released from noncoronary sources. Thus, it may be speculated that systemic inflammation precedes local inflammation at the plaques, thereby transforming coronary disease from a stable to an unstable form.

Endothelium-dependent vasodilatation in migraine patients.

Background: Endothelial dysfunction could be involved in the pathophysiology of migraine. The results obtained from a few studies on endothelial dysfunction in migraine are controversial. We investigated brachial flow-mediated dilatation (FMD), which reflects systemic endothelial dysfunction, in migraine patients without comorbidities. By employing strict inclusion criteria we avoided the possible changes to FMD from confounding factors. Methods. Forty migraine patients without comorbidities (20 with and 20 without aura) and 20 healthy subjects were included. FMD of brachial arteries and carotid intima-media thickness were measured by using standard procedures. Results. We did not find any difference in FMD between migraine patients and healthy subjects (p = .96). Also, no differences were found among healthy subjects, migraine patients with aura and without aura (p = .99). Conclusion. Our study showed that systemic endothelial function is not impaired in migraine patients without comorbidities, neither in those with or without aura. Considering these findings, the investigation of cerebral endothelial function would be useful in a further investigation of the role of endothelial (dys)function in migraine pathophysiology.