Arterial function is preserved in successfully treated patients with psoriasis vulgaris.

INTRODUCTION: Endothelial dysfunction is an early precursor of atherosclerosis and is common in patients with psoriasis, presumably primarily due to psoriasis-related inflammation. We investigated endothelial function, arterial stiffness, and circulating markers of endothelial activation in young patients with psoriasis vulgaris of varying severity, all of whom were effectively treated achieving PASI 90. METHODS: We conducted a cross-sectional study of 80 patients (54 men/26 women, 30-45 years) who were effectively treated with topical therapy, methotrexate, adalimumab, secukinumab or guselkumab, and 20 healthy controls. Endothelial dysfunction was measured by flow-mediated dilation and arterial stiffness was measured by pulse wave velocity and common carotid artery stiffness. The following circulating biomarkers of endothelial activation were measured: ICAM-1, VCAM-1, E- and P-selectin, GDF-15, and TRAIL. RESULTS: Endothelial function and arterial stiffness parameters did not differ between patients with effectively treated psoriasis and the control group. Circulating endothelial activation biomarkers did not show relevant differences between the groups of effectively treated patients or controls. DISCUSSION: Although cardiovascular disease is the leading cause of morbidity and mortality in patients with psoriasis, effective antipsoriatic treatment appears to slow the progression of atherosclerosis, even when there are cardiovascular risk factors, such as smoking or obesity. This may suggest that antipsoriatic treatment exerts a cardioprotective effect. CONCLUSIONS: Our results suggest that early and effective treatment of varying-severity psoriasis vulgaris in young patients appears to prevent arterial dysfunction related to psoriasis and consequent cardiovascular risk.The study is registered at http://clinicaltrials.gov (identifier: NCT05957120).

Residual metabolic burden in young psoriasis patients successfully treated with biologics.

Metabolic disorders are common in patients with psoriasis and contribute significantly to an increased cardiovascular risk. While biologic therapy is very successful in clearing skin lesions, its impact on metabolic parameters is uncertain. Our aim was to investigate the residual metabolic burden in psoriasis patients successfully treated with biologic therapy. We conducted a cross-sectional study of 80 young patients (54 men, 26 women, aged 30-45 years) successfully treated with either adalimumab, secukinumab or guselkumab and topical therapy or methotrexate, and 20 healthy controls. Anthropometric parameters, lipid levels and metabolic indices (HOMA-IR, TyG index and FIB-4 index) were measured. Patients did not receive any other treatments to exclude confounding effects. After analysis, we found that patients treated with three different biologics had similar metabolic status, only the FIB-4 index was higher in the adalimumab group than in the secukinumab and guselkumab treatment groups. There were no significant differences between the patients treated with biologics and the control group. The comparison with patients treated topically or with methotrexate showed that only triglyceride levels, HOMA-IR, TyG index, and FIB-4 index were elevated in patients treated with adalimumab compared to patients treated with topical therapy. Finally, metabolic status was also similar in patients treated with methotrexate or topical therapy. In conclusion, this study suggests that psoriasis patients successfully treated with biologics have similar metabolic parameters to the control group and patients treated with topical therapy or methotrexate. This indicates that there is no significant residual metabolic burden in young patients successfully treated with biologics. These results are clinically relevant and should be considered in the treatment of psoriasis patients.The study is registered at http://clinicaltrials.gov (identifier: NCT05957120). Date of registration: 24th of July 2023.

Obesity and Insulin Resistance in Asthma Pathogenesis and Clinical Outcomes.

Common inflammatory ground links obesity, insulin resistance, and asthma. As recognition of their interplay, one worsening the natural course of the other, is recognised, questions remain about how to adequately address them altogether to improve clinical outcomes. The present manuscript sheds light on the problem, describing possible pathophysiological links, clinical views, and therapeutic challenges, raising questions about what remains to be done, and calling for multidisciplinary treatment of these patients to detect diseases early and adequately address them before they become full-blown and deteriorate their health and quality of life.

Efficacy, safety, and patient satisfaction with oral semaglutide: first single-centre clinical experience.

OBJECTIVE: To explore the effects of oral semaglutide on glycaemic parameters, body weight, and satisfaction in the first recipient patients with type 2 diabetes mellitus in Slovenia, in a real-world clinical practice setting. METHODS: The first consecutive adult patients with type 2 diabetes who were eligible for oral semaglutide treatment were included in this prospective, open-label interventional study. Patients received increasing doses of oral semaglutide and were evaluated at inclusion, at 1 month, then 3-5 months after starting treatment. Fasting blood glucose, glycosylated haemoglobin (HbA1c), body weight, patient satisfaction with oral semaglutide treatment (using the validated Treatment Satisfaction Questionnaire for Medication), and adverse effects, were analysed. Statistical analyses were performed using one-way analysis of variance, and, when significant interactions were found, Bonferroni post-hoc test. A P-value <0.05 was considered statistically significant. RESULTS: Twenty patients (11 male: 9 female; mean age, 59.9 ± 1.5 years; mean diabetes duration, 8.5 ± 1.4 years) were included. Oral semaglutide (7 and 14 mg) significantly decreased HbA1c (from 9.4 ± 0.3% to 8.2 ± 0.2% and 7.8 ± 0.2%, respectively) and fasting plasma glucose (from 11.2 ± 0.5 mmol/L to 9.2 ± 0.7 mmol/L and 8.9 ± 0.4 mmol/L, respectively). Oral semaglutide (14 mg) significantly decreased body weight (from 100.9 ± 2.7 kg to 92.7 ± 2.4 kg). Patients reported that treatment was easy to use and expressed high global satisfaction. Mild and transient, mostly gastrointestinal, adverse effects were reported in 10 patients. CONCLUSIONS: Oral semaglutide, the first oral glucagon-like peptide 1 receptor agonist, was effective and safe, and associated with high patient satisfaction, in its first recipients in Slovenia. The results are important for daily clinical practice involving patients with type 2 diabetes, however, due to the small study population, lack of placebo control, and short exposure to oral semaglutide, the effectiveness of oral semaglutide in clinical practice requires further investigation.

Killing Two Birds with One Stone: Potential Therapies Targeting Psoriasis and Atherosclerosis at the Same Time.

Psoriasis is a chronic systemic inflammatory disease. Due to systemic inflammation, it is associated with many comorbidities. Among them, cardiovascular diseases represent the most common causes of morbidity and mortality in this population. Therefore, physicians treating patients with psoriasis should keep in mind that, as important as the treatment of psoriasis, awareness of cardiovascular risk deserves additional attention. Thus, in parallel with psoriasis treatment, a cardiovascular risk assessment must also be performed and addressed accordingly. In addition to encouraging non-pharmacologic strategies for a healthy lifestyle, physicians should be familiar with different pharmacologic options that can target psoriasis and reduce cardiovascular risk. In the present article, we present the pathophysiological mechanisms of the psoriasis and cardiometabolic interplay, our view on the interaction of psoriasis and cardiovascular disease, review the atherosclerotic effect of therapeutic options used in psoriasis, and vice versa, i.e., what the effect of medications used in the prevention of atherosclerosis could be on psoriasis.

Empagliflozin-Metformin Combination Has Antioxidative and Anti-Inflammatory Properties that Correlate with Vascular Protection in Adults with Type 1 Diabetes.

Methods: 40 individuals with type 1 diabetes (average age of 44.7 ± 2.5 years) were randomized into four groups: (1) control (placebo), (2) empagliflozin 25 mg daily, (3) metformin 2000 mg daily, and (4) empagliflozin-metformin combination (25 mg and 2000 mg daily, respectively). At inclusion and after 12 weeks of treatment, the blood samples were collected, and the oxidative stress (total antioxidative status (TAS), superoxide dismutase (SOD), glutathione peroxidase (GPx), uric acid, advanced oxidation protein products (AOPP), advanced glycosylation end products ((AGE) and isoprostane), and inflammation (C-reactive protein (CRP) and interleukin-6 (IL-6)) parameters were determined. Results: The empagliflozin-metformin combination increased levels of the antioxidants (TAS, SOD, and GPx up to 1.1-fold; P < 0.01), decreased the levels of prooxidants (AOPP and isoprostanes up to 1.2-fold, P < 0.01; AGE up to 1.5-fold, P < 0.01), and decreased inflammatory parameters (up to 1.5-fold, CRP P < 0.01; IL-6 P < 0.001). Antioxidative action was associated with the improvement in arterial function (obtained in the previous study) in the empagliflozin-metformin combination group. Conclusion: Empagliflozin-metformin combination has strong antioxidative and anti-inflammatory capacity, in adults with type 1 diabetes that is greater than that for the individual drugs. Its antioxidative activity at least partially explains the improvement in arterial function. Therefore, it appears that the combination provides the most powerful vascular protection.

Effect of Oral Semaglutide on Cardiovascular Parameters and Their Mechanisms in Patients with Type 2 Diabetes: Rationale and Design of the Semaglutide Anti-Atherosclerotic Mechanisms of Action Study (SAMAS).

INTRODUCTION: Type 2 diabetes (T2D) management has reached a point where not only optimal glycaemic control is necessary, but also additional interventions with proven cardiovascular risk reduction benefit. Subcutaneous semaglutide has been shown to provide cardiovascular protection, but its use may be limited by its injection formulation. To overcome this limitation, an oral semaglutide tablet has been developed, which could potentially be of the same value as its injection counterpart, but in a much wider group of patients with T2D, thereby allowing for broader cardiovascular risk reduction in this vulnerable patient population. METHODS: A total of 100 consecutive patients with T2D and a disease duration of up to 10 years, without manifest cardiovascular disease, who are treated with metformin (± sulphonylurea) and optimal cardioprotective therapy, will be recruited in a single-blinded, randomized trial named "Semaglutide Anti-atherosclerotic Mechanisms of Action Study (SAMAS)." After 1:1 randomization, patients will receive either oral semaglutide 14 mg daily or placebo for 1 year. The primary outcome comprises changes in atherosclerosis-related structural and functional characteristics of the arterial wall, namely: reduction of the carotid intima-media thickness, improvement of endothelial function and decrease in arterial stiffness. Secondary outcomes are changes in atherogenic small dense low-density lipoproteins, glucose control (HbA1c) and inflammatory markers (hsCRP). Possible correlations between primary endpoints and changes in lipids, HbA1c and high-sensitivity C-reactive protein will be sought. DISCUSSION: This is the first study to investigate the direct and indirect anti-atherosclerotic mechanisms of oral semaglutide. The results are expected to confirm the position of oral semaglutide in the multifactorial management of T2D with an emphasis on cardiovascular disease prevention. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05147896.

Treating Arterial Ageing in Patients with Diabetes: From Mechanisms to Effective Drugs.

Diabetes mellitus is a major healthcare problem. It is not only characterized by hyperglycemia and chronic complications, but in longer lasting diabetes and a longer living population, it is also associated with accelerated arterial ageing, which importantly contributes to cardiovascular complications. The accelerated arterial ageing in patients with diabetes should be considered separately from arterial ageing in patients without diabetes. Basic and clinical research have allowed better insight into the mechanisms of arterial ageing. In a simplified mechanistic way, it could be considered that the three tightly connected cornerstone characteristics of arterial ageing in patients with diabetes are: phenotypic presentation as endothelial dysfunction and arterial stiffness, and the underlying basic ageing-facilitating mechanism represented as the impaired expression of genetic longevity pathways. Currently, specific drugs for preventing/treating arterial ageing are not available. Therefore, we aimed to review the capacity of available drugs, particularly antidiabetic drugs, to interfere with the arterial ageing process. In the near future, these characteristics could help to guide therapy in patients with diabetes. Overall, it appears that arterial ageing could become a new target in diabetes. The expanding knowledge regarding the capability of antidiabetic drugs and other available drugs to inhibit/delay arterial aging is therefore essential.

Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat "Aging-Related Disorders".

The incidence of aging-related disorders may be decreased through strategies influencing the expression of longevity genes. Although numerous approaches have been suggested, no effective, safe, and easily applicable approach is yet available. Efficacy of low-dose fluvastatin and valsartan, separately or in combination, on the expression of the longevity genes in middle-aged males, was assessed. Stored blood samples from 130 apparently healthy middle-aged males treated with fluvastatin (10 mg daily), valsartan (20 mg daily), fluvastatin-valsartan combination (10 and 20 mg, respectively), and placebo (control) were analyzed. They were taken before and after 30 days of treatment and, additionally, five months after treatment discontinuation. The expression of the following longevity genes was assessed: SIRT1, PRKAA, KLOTHO, NFE2L2, mTOR, and NF-κB. Treatment with fluvastatin and valsartan in combination significantly increased the expression of SIRT1 (1.8-fold; p < 0.0001), PRKAA (1.5-fold; p = 0.262) and KLOTHO (1.7-fold; p < 0.0001), but not NFE2L2, mTOR and NF-κB. Both fluvastatin and valsartan alone significantly, but to a lesser extent, increased the expression of SIRT1, and did not influence the expression of other genes. Five months after treatment discontinuation, genes expression decreased to the basal levels. In addition, analysis with previously obtained results revealed significant correlation between SIRT1 and both increased telomerase activity and improved arterial wall characteristics. We showed that low-dose fluvastatin and valsartan, separately and in combination, substantially increase expression of SIRT1, PRKAA, and KLOTHO genes, which may be attributed to their so far unreported pleiotropic beneficial effects. This approach could be used for prevention of ageing (and longevity genes)-related disorders.

The influence of May-Thurner syndrome on post-thrombotic syndrome in young women.

Background: The mechanism for post-thrombotic syndrome (PTS), the most important long-term sequelae of deep venous thrombosis, is not entirely known. It is probably caused by venous hypertension due to venous insufficiency and venous obstruction. Venous hypertension could also be a consequence of the May-Thurner syndrome (MTS), i.e. the obstruction of the common iliac vein. The aim of the present study was to explore if women with untreated MTS and a history of proximal DVT develop PTS more frequently. Patients and methods: A cohort of 68 female patients with a history of proximal left-sided DVT in the past were evaluated. According to Villalta score, they were segregated in two groups - with and without PTS (Villalta score ≥ 5 or < 5 points, respectively). For the diagnosis of MTS, magnetic resonance venography was performed. Results: Out of 68 patients, 25 developed PTS (36.8 %). Recurrent DVT, older age, pre-existent chronic venous insufficiency, and shorter compression stockings wearing time were statistically related to PTS. Deep and superficial valve incompetence was also significantly related to PTS, while incomplete thrombus removal showed only a trend towards PTS development. On the other hand, MTS per se turned out not to be linked to PTS. Conclusions: Our study suggests that women with MTS might not develop PTS more often, which puts aggressive treatment of MTS under question. More clinical trials are warranted to further examine this yet not fully explained field.

Molecular Mechanisms Responsible for Diastolic Dysfunction in Diabetes Mellitus Patients.

In diabetic patients, cardiomyopathy is an important cause of heart failure, but its pathophysiology has not been completely understood thus far. Myocardial hypertrophy and diastolic dysfunction have been considered the hallmarks of diabetic cardiomyopathy (DCM), while systolic function is affected in the latter stages of the disease. In this article we propose the potential pathophysiological mechanisms responsible for myocardial hypertrophy and increased myocardial stiffness leading to diastolic dysfunction in this specific entity. According to our model, increased myocardial stiffness results from both cellular and extracellular matrix stiffness as well as cell⁻matrix interactions. Increased intrinsic cardiomyocyte stiffness is probably the most important contributor to myocardial stiffness. It results from the impairment in cardiomyocyte cytoskeleton. Several other mechanisms, specifically affected by diabetes, seem to also be significantly involved in myocardial stiffening, i.e., impairment in the myocardial nitric oxide (NO) pathway, coronary microvascular dysfunction, increased inflammation and oxidative stress, and myocardial sodium glucose cotransporter-2 (SGLT-2)-mediated effects. Better understanding of the complex pathophysiology of DCM suggests the possible value of drugs targeting the listed mechanisms. Antidiabetic drugs, NO-stimulating agents, anti-inflammatory agents, and SGLT-2 inhibitors are emerging as potential treatment options for DCM.

Prevention of Vascular Complications in Diabetes Mellitus Patients: Focus on the Arterial Wall.

In Diabetes Mellitus (DM), hyperglycaemia and insulin resistance progressively lead to both microvascular and macrovascular complications. Whereas the incidence of microvascular complications is closely related to tight glycaemic control, this does not apply to macrovascular complications. Hyperglycaemia influences many interweaving molecular pathways that initially lead to increased oxidative stress, increased inflammation and endothelial dysfunction. The latter represents the initial in both types of vascular complications; it represents the "obligatory damage" in microvascular complications development and only "introductory damage" in macrovascular complications development. Other risk factors, such as arterial hypertension and dyslipidaemia, also play an important role in the progression of macrovascular complications. All these effects accumulate and lead to functional and structural arterial wall damage. In the end, all factors combined lead to the promotion of atherosclerosis and consequently major adverse cardiovascular events. If we accept the pivotal role of vascular wall impairment in the pathogenesis and progression of microvascular and macrovascular complications, treatment focused directly on the arterial wall should be one of the priorities in prevention of vascular complications in patients with DM. In this review, an innovative approach aimed at improving arterial wall dysfunction is described, which may show efficacy in clinical studies. In addition, the potential protective effects of current treatment approaches targeting the arterial wall are summarised.

Empagliflozin on top of metformin treatment improves arterial function in patients with type 1 diabetes mellitus.

BACKGROUND: Deteriorated arterial function and high incidence of cardiovascular events characterise diabetes mellitus. Metformin and recent antidiabetic drugs, SGLT2 inhibitors, reduce cardiovascular events. We explored the possible effects of empagliflozin's effect on top of metformin treatment on endothelial function and arterial stiffness parameters in type 1 diabetes mellitus (T1DM) patients. METHODS: Forty T1DM patients were randomised into three treatment groups: (1) empagliflozin (25 mg daily), (2) metformin (2000 mg daily) and (3) empagliflozin/metformin (25 mg daily and 2000 mg daily, respectively). The fourth group received placebo. Arterial function was assessed at inclusion and after 12 weeks treatment by: endothelial function [brachial artery flow-mediated dilation (FMD), reactive hyperaemia index (RHI)], arterial stiffness [pulse wave velocity (PWV) and common carotid artery stiffness (ß-stiffness)]. For statistical analysis one-way analysis of variance with Bonferroni post-test was used. RESULTS: Empagliflozin on top of metformin treatment significantly improved endothelial function as did metformin after 12 weeks of treatment: FMD [2.6-fold (P < 0.001) vs. 1.8-fold (P < 0.05)] and RHI [1.4-fold (P < 0.01) vs. 1.3-fold (P < 0.05)]. Empagliflozin on top of metformin treatment was superior to metformin in improving arterial stiffness parameters; it significantly improved PWV and ß-stiffness compared to metformin [by 15.8% (P < 0.01) and by 36.6% (P < 0.05), respectively]. Metformin alone did not influence arterial stiffness. CONCLUSION: Empagliflozin on top of metformin treatment significantly improved arterial stiffness compared to metformin in T1DM patients. Endothelial function was similarly improved in all treatment groups. Empagliflozin seems to possess a specific capacity to decrease arterial stiffness, which could support its cardioprotective effects observed in large clinical studies. Trial registration Clinical trial registration: NCT03639545.

Improvement of arterial wall phenotype in subjects at moderate cardiovascular risk induced by very low-dose fluvastatin/valsartan combination: a pilot study.

BACKGROUND: The largest population that suffers from cardiovascular events are subjects at moderate cardiovascular risk. However, no effective and safe preventive treatment is available for this population. We investigated whether their arterial wall phenotype could be turned to a lower risk direction by low-dose fluvastatin/valsartan combination (low-flu/val). METHODS: Twenty males at moderate cardiovascular risk (as classified by SCORE) were blindly randomized into the intervention group (N.=10, low-flu/val: 10 mg/20 mg) or control group (N.=10, placebo). At inclusion and after 30 days of treatment, brachial flow-mediated dilatation (FMD), ß-stiffness coefficient, carotid pulse wave velocity (c-PWV), carotid-femoral PWV, Reactive Hyperemia Index, high-sensitivity C-reactive protein (hs-CRP), interleukin 6, vascular cell adhesion molecule 1, total antioxidant status and expression of several protective genes (SIRT1, mTOR, NF-κB1, NFE2L2, PRKAA1) were followed. RESULTS: Treatment resulted in improved FMD (from 3% to 4.2%, P=0.008), c-PWV (from 6.7 to 6.2 m/s, P=0.006), hs-CRP (from 5.39 to 3.35 mg/L, P=0.041) and SIRT1 expression (3.34-fold difference, P=0.047). No other vascular, inflammation and genetic parameters changed. The hs-CRP values after intervention correlated significantly with SIRT1 expression. The improved FMD persisted even 10 weeks after treatment discontinuation. The obtained changes were not followed by changes of lipids or blood pressure. Overall, the results revealed improvement in three different, although interrelated preventive arterial wall characteristics. CONCLUSIONS: This pilot study revealed that intervention with low-flu/val importantly shifts the arterial wall phenotype in a lower risk direction. This improvement could be interpolated into clinical benefits that remain to be further studied.

Sub-therapeutic doses of fluvastatin and valsartan are more effective than therapeutic doses in providing beneficial cardiovascular pleiotropic effects in rats: A proof of concept study.

BACKGROUND: Statins and sartans can, in therapeutic doses, induce pleiotropic cardiovascular effects. Similar has recently been shown also for sub-therapeutic doses. We thus explored and compared the cardiovascular pleiotropic efficacy of sub-therapeutic vs. therapeutic doses. METHODS: Wistar rats were randomly divided into 7 groups receiving fluvastatin, valsartan and their combination in sub-therapeutic and therapeutic doses, or saline. After 6weeks, the animals were euthanised, their hearts and thoracic aortas isolated, and blood samples taken. Endothelium-dependent relaxation of the thoracic aortae and ischaemic-reperfusion injury of the isolated hearts were assessed along with the related serum parameters and genes expression. RESULTS: Fluvastatin and valsartan alone or in combination were significantly more effective in sub-therapeutic than therapeutic doses. The sub-therapeutic combination greatly increased thoracic aorta endothelium-dependent relaxation and maximally protected the isolated hearts against ischaemia-reperfusion injury and was thus most effective. Beneficial effects were accompanied by increased levels of nitric oxide (NO) and decreased levels of asymmetric dimethylarginine (ADMA) in the serum (again prominently induced by the sub-therapeutic combination). Furthermore, nitric oxide synthase 3 (NOS3) and endothelin receptor type A (EDNRA) genes expression increased, but only in both combination groups and without significant differences between them. In the therapeutic dose groups, fluvastatin and valsartan decreased cholesterol values and systolic blood pressure. CONCLUSION: Sub-therapeutic doses of fluvastatin and valsartan are more effective in expressing cardiovascular pleiotropic effects than therapeutic doses of fluvastatin and/or valsartan. These results could be of significant clinical relevance.

Very low-dose fluvastatin-valsartan combination decreases parameters of inflammation and oxidative stress in patients with type 1 diabetes mellitus.

AIMS: Previously we revealed the effectiveness of a new therapeutic approach with a short-term, very-low dose fluvastatin-valsartan combination on the improvement of arterial function in type 1 diabetes mellitus patients (T1DM). In this study we explored whether this approach influences inflammation and oxidative stress and explored any association of these effects with arterial function improvement. METHODS: This was a supplementary analysis of the two previous double blind randomized studies (included 44 T1DM patients). Treatment group received very-low dose fluvastatin-valsartan, the control group received placebo. Blood samples were collected and inflammation parameters: high-sensitivity CRP (hsCRP), interleukin 6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1) and oxidative stress parameter total antioxidant status (TAS) were measured. RESULTS: Treatment decreased hsCRP values (by 56.5%, P<0.05) and IL-6 values (by 33.6%, P<0.05) and increased TAS values (by 21.1%; P<0.05) after 30days of treatment. High sensitivity CRP and TAS remained decreased 3months after treatment discontinuation. Importantly, the anti-inflammatory and anti-oxidative action significantly correlated with arterial function improvement. CONCLUSIONS: The approach consisting of short-term (30days) treatment with a very low-dose fluvastatin-valsartan combination acts anti-inflammatory and anti-oxidative in T1DM patients. These observations along with the improvement of arterial function support the assumption that this approach could have an important clinical benefit in T1DM patients.

The "Rise-Peak-Fall" Pattern of Time Dependency of the Cardiovascular Pleiotropic Effects of Treatment With Low-dose Atorvastatin, Losartan, and a Combination Thereof in Rats.

Treatment with low, subtherapeutic doses of statins and sartans expresses beneficial pleiotropic effects on the arterial wall. The present study explored whether these effects depend on treatment duration. Wistar rats were randomly divided into 4 groups and received low-dose atorvastatin, low-dose losartan, their combination, or saline (control) daily. After 4, 6, 8, and 10 weeks of treatment, the animals were anesthetized, blood samples taken, and hearts and thoracic aortas isolated. Thoracic aorta endothelium-dependent relaxation and parameters of the isolated heart exposed to ischemic-reperfusion injury were assessed along with blood serum parameters and vasoactive genes expression. Low-dose atorvastatin, losartan, and especially their combination showed the characteristic time dependency of all studied parameters (thoracic aorta relaxation, isolated heart parameters, C-reactive protein values, genes encoding endothelial nitric oxide synthase, and CD40). The peak in efficacy was observed after 6 weeks of treatment and subsequently steadily declined. The peak versus control values were significant for all measured parameters. Only a combination of atorvastatin and losartan increased nitric oxide and decreased asymmetric dimethylarginine. A characteristic time-dependent "rise-peak-fall" pattern of the cardiovascular pleiotropic effects of statins and sartans in subtherapeutic low doses was revealed. Evidently, resistance to the explored treatment occurs after a certain period.

Low-Dose Fluvastatin and Valsartan Rejuvenate the Arterial Wall Through Telomerase Activity Increase in Middle-Aged Men.

BACKGROUND AND AIM: Previously, we have shown that slightly to moderately aged arteries in middle-aged males can be rejuvenated functionally by sub-therapeutic, low-dose fluvastatin and valsartan treatment. Here, we explore whether this treatment could also increase telomerase activity. We hypothesized that telomerase activity might be associated with (1) an improvement of arterial wall properties and (2) a reduction of inflammatory/oxidative stress parameters (both observed in our previous studies). METHODS: The stored blood samples from 130 apparently healthy middle-aged males treated with fluvastatin (10 mg daily), valsartan (20 mg daily), fluvastatin and valsartan combination (10 and 20 mg), respectively, and placebo (control), were analyzed. The samples were taken before and after treatment lasting 30 days, and 5 months after treatment discontinuation. Telomerase activity was measured in blood leukocytes by a TaqMan Gene Expression Assay. RESULTS: Low-dose fluvastatin or valsartan increased telomerase activity (106.9% and 59.5% respectively; both p < 0.05, vs. control), whereas their combination was even more effective (an increase of 228.0%; p < 0.001, vs. control). No change was noted in the control group. Importantly, increased telomerase activity obtained in the combination group significantly correlated with arterial function, measured by flow-mediated dilation (FMD) (r = 0.79; p < 0.001) and C-reactive protein concentration (r = -0.54; p = 0.02) and total anti-oxidative status (r = 0.50; p = 0.03). CONCLUSION: We found that a low-dose combination of fluvastatin and valsartan substantially increased telomerase activity, which significantly correlated with an improvement of endothelial function and a decrease of inflammation/oxidative stress. These findings could lead to a new innovative approach to arterial rejuvenation.

Long-term improvement of arterial wall characteristics in patients with diabetes mellitus type 1 using cyclic, intermittent treatment with a low-dose fluvastatin and valsartan combination.

Improvement of arterial wall (AW) characteristics decreases cardiovascular risk. In a previous study, it was observed that AW characteristics in patients with diabetes mellitus type 1 are significantly improved by short-term treatment with a low-dose combination of fluvastatin and valsartan. Additionally, a unique phenomenon of prolonged effect after treatment discontinuation was suggested. The present study tested whether repeated treatm ent after a certain period results in the same beneficial effect, th ereby advancing the hypothesis that cyclic treatment can provide a long-term improvement of AW characteristics. A total of 44 patients with diabetes mellitus type 1 that participated in the previous study were recruited. Six months after the discontinuation of the initial treatment, the same treatment with a low-dose fluvastatin (10 mg daily) and valsartan (20 mg daily) combination (n=22) or placebo (n=22) was repeated. Brachial artery flow-mediated dilation (FMD), pulse wave velocity (PWV) and carotid artery ß-stiffness were measured. It was found that the beneficial effect achieved with an initial 1-month treatment was completely regained following treatment repetition: FMD improved by 50.9% (P<0.01), PWV by 5.7% (P<0.001) and ß-stiffness by 9.9% (P<0.001). In addition, a gradual decline of the obtained effects was observed, reaching the level of 9.6% for FM D, 6.3% for PWV and 9.5% for ß-stiffness 6 months after treatm ent discontinuation. It was observed that repetition of treatment was similarly effective as the initial intervention. The benefits achieved by treatment steadily declined with time. Combining these findings, cyclic intermittent treatment with a low-dose fluvastatin and valsartan combination is proposed as a new cardiovascular preventive strategy in patients with DM1.

A low-dose combination of fluvastatin and valsartan: a new "drug" and a new approach for decreasing the arterial age.

We have developed a new "drug" and approach that appear to be effective in reducing arterial age. This "drug" represents a low, subtherapeutic dose of statin and sartan and particularly their low-dose combination. The improvement of arterial wall characteristics, also reflecting in a decrease of arterial age, was achieved after a short period of treatment (one month) with the above-mentioned drugs. In addition, we have also implemented a new, innovative therapeutic approach, consisting of intermittent (cyclic) treatment-alternating short "treatment" periods and much longer "rest" periods (when the beneficial effects are still present but gradually decline). This new "drug" and approach both merit further investigation in order to confirm their antiaging efficacy.