Miodrag Janić

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).

Subtherapeutic, low-dose fluvastatin improves functional and morphological arterial wall properties in apparently healthy, middle-aged males--a pilot study.

OBJECTIVE Early arterial wall changes are already present in the apparently healthy, middle-aged population and continuously progress with age. The aim of our study was to investigate whether 30 days low-dose fluvastatin treatment could improve and reverse these arterial changes that are primarily associated with ageing, in otherwise healthy middle-aged males. METHODS In a double blind, randomized study, 50 middle-aged males received either placebo or fluvastatin (10mg) for 30 days. Brachial artery flow-mediated dilation (FMD), pulse wave velocity (PWV) and β-stiffness of the common carotid artery were measured on the 1st, 14th and 30th day of the study using an Aloka instrument by integrated eTracking. RESULTS In 77% of subjects, impaired endothelial function was revealed at inclusion in the study. All the parameters were improved already after 14 days, and after 30 days of treatment FMD improved by 91.5 ± 15.6%, while PWV and β-stiffness improved by 6.2 ± 1.1% and 10.7 ± 1.5%, respectively (all P<0.001). After therapy discontinuation, the beneficial effects progressively decreased, but were still detectable after 5 months. During the study the lipid profile remained unchanged, thus the beneficial effects obtained were attributed to the pleiotropic effects of fluvastatin. CONCLUSIONS We found that subtherapeutic low-dose fluvastatin (10mg daily; 30 days) considerably improves and reverses early functional and morphological arterial wall impairments that are present in apparently healthy, middle-aged males. It might be supposed that such a new and original approach could be valuable in cardiovascular prevention.

Reduction of age-associated arterial wall changes by low-dose valsartan

Background: Functional and morphological arterial wall impairment progresses with ageing. Angiotensin II in the arterial wall is involved in this process. Appropriate early intervention might theoretically slow the progress of age-related changes. Herein, we investigated a new approach to this issue: whether arterial wall changes present in middle-aged males could be reduced by low-dose valsartan intervention. Methods: Forty apparently healthy, middle-aged males (42.9 ± 0.9 years) were recruited for a double-blind randomized study and received either placebo or valsartan (20 mg daily) for 30 days. Brachial artery flow-mediated dilation (FMD), pulse wave velocity (PWV), and β-stiffness of the common carotid artery were measured using an Aloka alfa-10 Prosound with an integrated eTracking system at inclusion, after 30 days, and after 3 and 8 months. Results: Intervention resulted in FMD increase (154.2 ± 20.1 %; p < 0.001) and PWV and β-stiffness decrease compared to initial values (−6.9 ± 1.0 % and −13.2 ± 1.4 %; both p < 0.01) whereas values in the untreated group (p < 0.001 for all parameters) remained unchanged throughout the study. The advantageous effects decreased over the months following valsartan discontinuation, but were still significant after 3 months (largely in FMD and less in PWV and β-stiffness), and negligible after 8 months. The beneficial effects were ascribed to valsartans pleiotropic effects, as no blood pressure changes were recorded. Conclusions: We showed that age-related arterial wall changes in middle-aged males are reversible and could be reduced by a low-dose, short-term valsartan intervention. The new approach merits detailed investigation in future studies.

Improvement of arterial wall characteristics by the low-dose fluvastatin and valsartan combination in type 1 diabetes mellitus patients

We tested whether short-term, low-dose treatment with the fluvastatin and valsartan combination could improve impaired arterial wall characteristics in type 1 diabetes mellitus patients. A total of 44 type 1 diabetes mellitus patients were randomised into the treatment group [n = 22; received a low-dose combination of fluvastatin (10 mg daily) and valsartan (20 mg daily)] and the control group (n = 22; received placebo), both for 30 days. Brachial artery flow-mediated dilation (FMD), pulse wave velocity (PWV) and carotid artery β-stiffness were measured. Significant improvements in FMD (+73.2%), PWV (−7.5%) and β-stiffness (−10.0%) were achieved after 1-month treatment compared to the control group (all p values < 0.001). Three months after therapy discontinuation, important residual improvement in measured parameters was still present. No changes in lipids and blood pressure accompanied the beneficial improvements. We conclude that relatively simple intervention (low-dose, short-term fluvastatin/valsartan combination) produces substantial, long-term improvement of arterial wall characteristics in type 1 diabetes mellitus patients.

A Combination of Low-Dose Fluvastatin and Valsartan Decreases Inflammation and Oxidative Stress in Apparently Healthy Middle-Aged Males

PURPOSE: We have previously shown that a “short-term, low-dose” treatment approach with statins, angiotensin receptor blockers, and especially their low-dose combination, is effective in improving arterial wall properties in apparently healthy middle-age men. This study was performed to expand investigation of its effects on inflammation and oxidative stress. METHODS: The study was performed supplementary to 3 previous studies, overall 65 treated participants (25 received fluvastatin 10 mg, 20 valsartan 20 mg, 20 their combination) and 65 participants placebo. The stored blood samples (collected at inclusion and after 30 days of treatment) were used to measure high-sensitivity CRP, interleukin-6, vascular cell adhesion molecule-1, total antioxidant status, glutathione peroxidase, and selenium concentration. RESULTS: A low-dose combination decreased inflammation parameters (high-sensitivity CRP: from 1.2 ± 0.1 to 0.7 ± 0.1 mg/L; P < .001; vascular cell adhesion molecule-1: from 523 ± 21 to 482 ± 12 pg/mL; P < .05; while interleukin-6 did not reach the level of significance). It also increased antioxidant defenses, as measured by total antioxidant status and glutathione peroxidase (from 1.4 ± 0.04 to 1.5 ± 0.04 mmol/L; P < .01, and from 1.2 ± 0.06 to 1.4 ± 0.06 &mgr;kat/g hemoglobin; P < .05, respectively), accompanied by decreased selenium levels. Low-dose valsartan was separately less effective than the combination. No changes were observed in the control groups. CONCLUSIONS: Low-dose combination of fluvastatin and valsartan and, to a lesser extent low-dose valsartan alone, produced important anti-inflammatory and anti-oxidative effects. These results confirm and extend the potential of the “short-term, low-dose” preventive strategy.

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.

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.

Abstract: 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.

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.