New pharmacological approaches targeting arterial stiffness






Harry A. J. STRUIJKER-BOUDIER, PhD
Department of Pharmacology and Toxicology
Cardiovascular Research
Institute Maastricht
Maastricht University
THE NETHERLANDS

New pharmacological approaches targeting arterial stiffness


by H. A. J. St ruijker-Boudier, The Netherlands



Arterial stiffness is an independent risk factor for the development of cardiovascular morbidity and mortality. When arterial “destiffening” strategies emerged, they were originally based on the use of antihypertensive drugs; however, in the last decade, alternative strategies not based upon blood pressure lowering have been developed. This article reviews the major recent developments in this field, discussing a diverse range of drug classes with respect to their destiffening properties. These drug classes include nitric oxide (NO) donors, lipid-lowering drugs, antidiabetic agents, angiotensin II type 2 receptor agonists, anti-inflammatory drugs, antiviral and antibiotic drugs, hormone replacement therapy, and drugs influencing calcium and phosphate metabolism. While the evidence for some of these drugs rests only upon studies in experimental animals, for other therapies there is convincing clinical evidence. However, further developmental studies are needed. With the important cardiovascular risk associated with arterial stiffening, the clinical need for effective destiffening therapies remains. The most promising areas to develop future arterial destiffening drugs appear to include NO donors, drugs interfering with the arterial extracellular matrix, anti-inflammatory drugs, and agents reducing arterial calcification.

Medicographia. 2015;37:421-426 (see French abstract on page 426)



Arterial stiffness has emerged as a risk factor for cardiovascular morbidity and mortality. Initially, it was particularly associated with hypertension, but research over the past two decades has revealed its importance in other diseases, such as coronary heart disease, diabetes, and metabolic syndrome (for a review, see reference 1). The important role of arterial stiffness in the etiology of cardiovascular and metabolic diseases raises the question whether arterial stiffness can be a target for drug- or nutrition-based interventions. Other articles in this journal issue describe the various indices used to assess arterial stiffness. Some of these indices (eg, arterial distensibility) are blood pressure–dependent, whereas others give a measure of the material properties of the arterial wall.2 That distinction is important when discussing the effects of pharmacological interventions on arterial stiffness. For instance, a drug-induced reduction in blood pressure may influence arterial distensibility without a direct effect on the material properties of the arterial wall. This article will focus on the blood pressure–independent effects of drugs on arterial stiffness. As the effects of non-antihypertensive drugs have already been reviewed by Boutouyrie et al3 in 2011, I will focus on more recent data concerning the effects of different non-antihypertensive drugs on arterial stiffness.

Nitric oxide donors

Most antihypertensive vasodilators selectively dilate small resistance arteries and arterioles, thereby reducing blood pressure. Notable exceptions are the organic nitrates, which are selective dilators of muscular conduit arteries.4,5 In a recent study, Omar et al6 showed that nitrite in near physiological concentrations selectively dilates conduit arteries and reduces central blood pressure. This effect involves cyclic guanosine monophosphate (cGMP) production. Similar evidence for a role of cGMP in influencing arterial stiffness comes from a study by Aversa et al7 who showed that vardenafil—a selective inhibitor of phosphodiesterase 5, an enzyme which catalyzes the breakdown of cGMP—improves arterial stiffness in patients with erectile dysfunction. Furthermore, a study by Isabelle et al8 in spontaneously hypertensive rats showed that long-term reduction in nitric oxide (NO) levels increases aortic stiffness. In addition to the enhanced production of cGMP by NO donors, a normalization of the formation of advanced glycation end products (AGEs) has been proposed as a mechanism of sodium nitrite “destiffening” of large arteries.9 Altogether, these data make NO donors as well as the emerging synthetic soluble guanylate cyclase stimulators attractive candidates for arterial destiffening.

Lipid-lowering drugs

In their 2011 review, Boutouyrie et al3 discussed the controversies concerning a number of studies on the effects of statins on aortic stiffness. They concluded that these effects, if any, are not clinically significant. A systematic review of the early published trials on statins and arterial stiffness showed that when pulse wave velocity (PWV) was used, only 2 of 4 trials showed destiffening with statins.3,10 However, when peripheral indices of arterial stiffness were used, 4 out of 5 trials showed positive results.3,10 In two recent studies, fluvastatin11 and atorvastatin12 were shown to reduce carotid arterial stiffness.

As suggested by Boutouyrie et al,3 statin-induced improvement in arterial stiffness may be more marked in the context of inflammation. Furthermore, Wallace et al13 have shown that simvastatin reduces inflammation-induced aortic stiffening and endothelial dysfunction. More recently, Wang et al14 observed an improvement in arterial stiffness through reduction in oxidative stress damage in elderly hypertensive patients after 6 months of atorvastatin therapy.




Antidiabetic drugs

Diabetes mellitus is associated with increased arterial stiffness, independently of blood pressure changes.15 Various cardiovascular risk factors have been implicated in the increased stiffness in diabetes, such as increased sympathetic tone, increased activity of the renin-angiotensin system, and the formation of AGEs.16

Inhibition of AGE formation
AGEs are nonenzymatically derived glycation products of proteins, in particular, collagen. This leads to the formation of collagen cross-links and arterial stiffening. Early evidence for a role of AGE formation came from a study in diabetic rats in which aminoguanidine—an inhibitor of AGE formation— increased elasticity of large arteries.17 In this experimental model of diabetes, the same group later showed that the collagen cross-link breaker alagebrium (ALT 711) decreases large artery stiffness.18 These animal studies were confirmed by clinical observations in hypertensive patients with diabetes.19 In a rat model for aging, alagebrium reduced arterial stiffness, in particular when combined with regular physical exercise.20 However, these data could not be confirmed in normotensive, nondiabetic elderly humans.21 Recent support for the potential of AGEs as a target for arterial destiffening comes from observations on the soluble receptor for AGEs (sRAGE).22,23 High plasma levels of sRAGE are associated with incident fatal and nonfatal cardiovascular disease and all-cause mortality in individuals with type 1 diabetes. sRAGE-associated aortic stiffening may partially explain this association.23

Glitazones
Other drugs used in the treatment of diabetes have been investigated with respect to their arterial destiffening activity. Boutouyrie et al3 have reviewed the early evidence that the glitazones in particular can decrease aortic stiffness. They proposed that this effect could be related to the increase in adiponectin in both diabetic and hypertensive patients. Recent studies24,25 have confirmed that pioglitazone improves aortic stiffness in patients with rheumatoid arthritis.

Modulation of incretin-receptor signaling
Drugs interacting with incretin-receptor signaling have recently been studied. Sitagliptin, when added to metformin-treated type 2 diabetes patients, did not significantly affect arterial stiffness.26 Also, the glucagon-like peptide-1 receptor agonist liraglutide, on top of metformin therapy, did not cause a change in arterial stiffness parameters.27 Earlier studies had already shown that metformin can reduce aortic stiffness in young women with polycystic ovary syndrome.28 The new class ofsodium glucose transport inhibitors, including dapagliflozin29 and empagliflozin,30 has been shown to have a favorable effect on arterial stiffness in diabetic subjects.

Angiotensin II type 2 receptor agonists

Most of the well-known effects of angiotensin II (Ang II) are mediated via the Ang II type 1 (AT1) receptor. Increasing evidence over the past years suggests that Ang II type 2 (AT2) receptors mediate vasculoprotective actions via vasodilation, NO production, and inhibition of cell growth and fibrosis. Recent studies in spontaneously hypertensive rats show that the selective AT2 receptor agonist Compound 21 (C21) reduces arterial stiffness as well as aortic medial and myocardial collagen content, and aortic fibronectin.31 In Nw-nitro-L-arginine methyl ester hydrochloride (L-NAME)–treated hypertensive rats, C21 prevented aortic stiffening and collagen accumulation without preventing the development of hypertension.32 It has been suggested that extracellular matrix metalloproteinases (MMPs) play an essential role in AT2 receptor–mediated effects on cardiac and vascular stiffness.33 Further clinical studies are needed to confirm a potential role of AT2 receptors in arterial stiffness in humans.

Anti-inflammatory drugs

Inflammation may be an essential mechanism of increased arterial stiffness in diseases such as rheumatoid arthritis34 or inflammatory bowel disease.35 Some authors have suggested a role for chronic low-grade inflammation in the increased arterial stiffness in hypertension.36 In early evidence for arterial destiffening by anti-inflammatorydrugs, reviewed by Boutouyrie et al,3 antibodies against tumor necrosis factor α (TNF-α) were shown to improve arterial stiffness, independently of any change in blood pressure, in patients with different chronic inflammatory diseases.3 Recent studies confirmed this positive effect of anti–TNF-α in a wide range of chronic inflammatory diseases.37-40 Furthermore, Angel et al41 showed that anti–TNF-α therapy improved the L-arginine to asymmetric dimethylarginine ratio in patients with inflammatory arthropathies. This raises the interesting possibility that similar mechanisms may reduce the inflammatory process occurring in atherosclerosis. Previous studies had already suggested that statins exhibit destiffening properties only in the presence of inflammation.3 Additional studies including the effect of classical nonsteroidal anti-inflammatory drugs would offer a more complete picture of the effect of anti-inflammatory drugs on destiffening.

Antiviral and antibiotic drugs

Antiviral therapy
Individuals infected with the human immunodeficiency virus (HIV) have an increased risk of atherosclerosis and cardiovascular disease, which has been attributed to higher prevalence of traditional cardiovascular risk factors, HIV itself, as well as antiviral therapy.42,43 Emerging evidence suggests that HIVinduced T-cell activation, which remains abnormally elevated even after viral suppression with highly active antiretroviral therapy, is associated with an increase in arterial stiffness.42 Activated T cells are markers of inflammation, and this may contribute to arterial stiffening, as discussed above. When antiretroviral therapy is initiated in HIV-infected subjects at the moment of high nadir T-cell counts, a reduction in arterial stiffness is observed.44 Since antiretroviral drugs are typically prescribed in cocktails of 3 different drugs, it is difficult to establish the role of specific agents in the development of arterial stiffness. One of the most frequently used antivirals, azidothymidine, was shown to increase arterial stiffness in mice.45

Antibiotic therapy
There are no systematic studies on the effects of different antibiotic drug classes on arterial stiffness. Some authors reported that low-to-moderate–dose anthracycline-based chemotherapy increases arterial stiffness.46,47 However, there are several reports that doxycycline protects against the structural vascular alterations associated with hypertension, including arterial stiffness (for a review, see reference 48). Doxycycline acts at low doses to inhibit matrix MMPs. In view of the important role of MMPs in vascular remodeling, further studies on the effects of doxycycline and related MMP inhibitors are needed.

Hormone replacement therapy

In their review, Boutouyrie et al3 summarized the results of 13 relevant randomized controlled trials on hormone replacement therapy and arterial stiffness. Negative results were observed with all modalities of hormone replacement therapy: estrogen alone or in combination with the selective estrogen receptor modulator raloxifene.49 In a recent comprehensive multicenter trial, Gompel et al50 showed that hormone replacement therapy in postmenopausal women is associated with lower values of carotid artery intima-media thickness, central pulse pressure, and aortic stiffness, independently of age at menopause and the time since menopause. Matsui et al51 reported that ultra-low-dose estradiol (0.5 mg) and dydrogesterone (5 mg) every day for 1 year decreased brachialankle PWV and vascular inflammatory markers. A recent trial52 on the sex hormone precursor dehydroepiandrosterone (DHEA) in older adults showed that DHEA reduced the carotid augmentation index and carotid-femoral artery PWV. This effect was accompanied by a decrease in serum inflammatory cytokines. Altogether, the issue whether hormone replacement therapy has a favorable effect on arterial stiffness remains enigmatic with various confounding factors, eg, dose, duration, and nature of the therapy.

Drugs influencing calcium and phosphate metabolism

Calcium metabolism modulation
Since calcification of the arterial wall is an important event in arterial aging and stiffening, targeting calcium metabolism looks to be an attractive therapeutic option. The literature on cardiovascular consequences of calcium supplementation isfull of controversies, some claiming beneficial effects, others claiming the opposite (for a review, see reference 53). Since vascular calcification is more common in hemodialysis patients, it has been suggested that repeated episodes of hypercalcemia can increase the risk of vascular calcification and arterial stiffening.54 Bisphosphonates are considered first-line therapy in osteoporosis. They inhibit bone resorption by an action on osteoclasts in which they form tight complexes with calcium in the bone matrix. Recent studies suggest their potential to reduce atherosclerosis owing to a similar effect on calcium release in the vessel wall.55 A recent study shows that bisphosphonate treatment in women with postmenopausal osteoporosis reduces arterial stiffness.56 This interesting observation needs follow-up.

Phosphate metabolism modulation
Phosphate is another mineral that plays an important role in skeletal remodeling, with particular action in the chronic kidney disease–mineral and bone disorder (CKD-MBD),57 in which increased vascular stiffness is a main feature. Recent studies have shown that sevelamer, a non–calcium-based phosphate binder has a favorable effect on arterial stiffness in patients with chronic kidney disease58 and in mice with chronic renal failure.59

Other drugs

In addition to the above described drug classes, incidental observations were made in experimental animal models on destiffening effects of the cardiac pacemaker current (If) inhibitor ivabradine60 and the 5-lipoxygenase inhibitor caffeic acid phenethyl ester.61 Also, clinical observations suggest that uric acid–lowering therapy with allopurinol62 or febuxostat63 reduces arterial stiffness. However, these incidental observations need further confirmation.

Conclusion

In conclusion, whereas the original approach to arterial destiffening was primarily focused on antihypertensive drugs, we now see various leads to drugs that lower arterial stiffness without affecting blood pressure. The most promising leads are in the area of NO donors and drugs that interfere with the arterial extracellular matrix, eg, inhibitors of AGE formation and drugs interfering with the metabolism of MMPs. Other potential areas that need further study are anti-inflammatory drugs and drugs affecting arterial calcification. Given the important cardiovascular risk associated with arterial stiffening, the clinical need for destiffening therapies remains significant.


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Keywords: arterial stiffness; destiffening; diabetes; drug treatment; extracellular matrix; hypertension