Can Antihypertensive Medication Interfere with the

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Abstract Vascular calcification is a phenomenon of disturbed calcium deposition, as part ... Angiotensin converting enzyme inhibitors . Angiotensin receptor ... bone morphogenetic protein (BMP-2), osteopontin (OPN) and increase expression ...

Can Antihypertensive Medication Interfere with the Vicious Cycle Between Hypertension and Vascular Calcification? Maria I. Pikilidou, Maria P. Yavropoulou & Angelo Scuteri

Cardiovascular Drugs and Therapy ISSN 0920-3206 Cardiovasc Drugs Ther DOI 10.1007/s10557-013-6494-5

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Author's personal copy Cardiovasc Drugs Ther DOI 10.1007/s10557-013-6494-5


Can Antihypertensive Medication Interfere with the Vicious Cycle Between Hypertension and Vascular Calcification? Maria I. Pikilidou & Maria P. Yavropoulou & Angelo Scuteri

# Springer Science+Business Media New York 2013

Abstract Vascular calcification is a phenomenon of disturbed calcium deposition, as part of the calcium that is supposed to be deposited to our bones, is lodged to our vessels. There are two forms of vascular calcification, each with a distinct anatomical distribution and clinical relevance, namely the intimal and medial calcification. Studies have demonstrated that hypertension may cause vascular calcification but also that both types of calcification, especially medial, promote arterial rigidity and hence hypertension. Implications of this two-way road are largely unknown as there is no consensus yet on their exact clinical value. However, several antihypertensive medications seem to be able to interfere with the cycle of high blood pressure and vascular calcium deposits. The present review summarizes the up-to-date data regarding the effect of antihypertensive medication on vascular calcification. Keywords Vascular calcification . Antihypertensive medication . Angiotensin converting enzyme inhibitors . Angiotensin receptor blockers . Calcium channel blockers

Introduction For years vascular calcification (VC) has been considered an immutable passive procedure with unknown effects on the M. I. Pikilidou (*) Hypertension Excellence Center, 1st Department of Internal Medicine, AHEPA University Hospital, St. Kiriakidi 1, 54636 Thessaloniki, Greece e-mail: [email protected] M. P. Yavropoulou Division of Endocrinology and Metabolism, 1st Department of Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece A. Scuteri Hospital San Raffaele Pisana IRCCS, Rome, Italy

cardiovascular system. Today, more light has been shed in understanding its formation mechanisms. Evidence shows that VC is a process highly regulated, involving a number of pro- and anti-calcification mediators and that it resembles natural bone formation [1]. There are two forms of VC, each with a distinct anatomical distribution and clinical relevance namely the intimal and medial calcification, the latter more widely known as medial elastocalcinosis or Mockenberg’s disease [2]. Current guidelines recommend the use of coronary artery calcification (CAC) scoring for intermediate risk patients [3]. For this purpose coronary computed tomographic angiography (CCTA), is being widely used in clinical practice for the diagnosis of coronary artery disease [4]. The product of the density of the calcium and the area of the calcium in the artery is the Agastson score, now largely used to quantify CAC. An Agastson score of >400 indicates increased risk for cardiovascular events [5]. Intimal calcification involves the lipid rich fibrous cap of the atheroma and is likely to be the net result of a balance of factors favoring and inhibiting calcification. The former factors include apoptotic cell death of vascular smooth muscle cells (VSMCs) and macrophages, calcification stimulatory proteins, lipids, and mechanisms which increase the extracellular concentration of calcium and phosphate while the latter factors include phagocytosis, calcification inhibitory proteins and potentially osteoclast macrophages [6]. The contribution of intimal calcification to plaque rupture is controversial. The “living proof” of this controversy is the predictive value of the CAC, for which some evidence has shown to add incremental value in predicting all cause mortality beyond prediction scores, demographics and cardiovascular risk factors [7], while on the other hand, a CAC score of 0 does not mean that coronary artery disease is absent, especially in young individuals who may have soft, fatty atheromas [8]. Also, several studies have reported the presence of obstructive, non-calcified plaque in up to 8.7 % in asymptomatic patients with zero or low calcium score [9, 10].

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Medial elastocalcinosis is a less frequent phenomenon and characterizes mainly diabetic and chronic kidney disease patients. Unlike intimal calcification, medial calcification occurs in the absence of lipids or inflammatory cells. It is likely the result of a lack of expression or activity of calcification inhibitory proteins, degeneration of elastic fibers, induction of apoptosis and failure of clearance of apoptotic bodies, or a de-regulation of pH [6]. This type of calcification promotes vascular rigidity and hence hypertension, but it is not distinguishable from intimal calcification by current imaging techniques. In chronic kidney disease, dysregulation of calcium and phosphate metabolism is common and drives VC through direct effects on vascular smooth muscle cells (VSMCs) including stimulation of osteogenic/chondrogenic differentiation, vesicle release, apoptosis, loss of inhibitors and extracellular matrix degradation [11]. In diabetes, free radicals induce the development of chronic inflammation in the adventitia, leading to the infiltration of connective tissue by macrophages and lymphocytes. Glycosylation end products (AGEs) increase tumor necrosis factor a (TNF-a), osteogenic growth factor bone morphogenetic protein (BMP-2), osteopontin (OPN) and increase expression of msh homeobox homolog 2 (Msx-2) gene leading to intramembranous bone formation [12]. Hypertension induces the arterial stiffness phenotype— which reflects the aging vasculature—and is thought to be the combination of two culprits: fibrosis and/or calcification. Often, these two coexist, with recent evidence supporting that, chronologically, calcification comes second. It seems that fibrosis through the production of elastin fragments generation increases proteases activity and activation of transforming growth factor-b (TGF-b) signalling, and together with deposition of collagen and proteoglycans is thought to generate a permissive soil for VC within the medial layer of the vessels (elastocalcinosis) [13]. Both intimal and medial calcification could increase vascular stiffness, although their relative contribution to arterial rigidity is still unknown [13]. In turn, arterial stiffness promotes blood pressure increase since incompliant arteries cannot expand with pressure changes creating the high pulse pressure phenotype [14]. Hence hypertension and VC represent two interrelated processes possibly “stuck” in the vicious cycle of hypertensive arterial calcification and arterial stiffness-induced high blood pressure [13]. Despite the fact that exact relations between these two phenomena are yet to be clarified, attempts have been made recently in order to identify therapeutic strategies to interrupt this vicious cycle. The present review will summarize existing evidence regarding the effect of antihypertensive medication in the process of VC.

Methods Between May 2012 and 18 October 2012 (last date searched) we comprehensively searched the following databases: Medline (1950 to present), EMBASE (1980 to present), the Cochrane Library (1960 to present), Scopus (1996 to present), Web of knowledge (1970 to present). The search included original articles using the terms “vascular calcification” OR “coronary calcification”, AND each time including one of the following terms “antihypertensive medication”, “calcium channel blocker”, “angiotensin receptor blocker”, “angiotensin converting enzyme inhibitors”, “diuretics”, “α-blockers”, “β-blockers”, “magnesium”, “endothelin antagonists”. The terms “β-blockers”, “αblockers”, “diuretics” and “central acting agents” combined with “vascular calcification” retrieved no relevant results. Bibliography from references and citations of relevant articles was also retrieved. The search included studies of the effect of antihypertensive medication on the calcification of human vessels and those of experimental animal models as well as the effect of antihypertensive treatment on the calcification properties of endothelial cells and VSMCs .

Calcium Channel Blockers (CCBs) Tables 1, 2 and 3 summarize the studies investigating the impact of antihypertensive treatment on vascular calcification in humans and experimental models. The first study in humans to demonstrate an effect of CCBs on VC was a side arm of the International Nifedipine Study: Intervention as Goal for Hypertension Therapy (INSIGHT). In this study, nifedipine inhibited the progression of coronary calcium in a subgroup of 201 high-risk hypertensive patients compared to co-amilozide (3.18 % versus 27 %, respectively, P =0.02) after 3 years of treatment [15]. The clinical message of this study however is not entirely clear in the light of the results of INSIGHT which showed equal effectiveness of nifedipine once daily and co-amilozide in preventing overall cardiovascular or cerebrovascular complications. Since then, studies in experimental animal models have explored the effects of CCBs on VC. Specifically, Essahili et al., showed that amlodipine prevented aortic medial elastocalcinosis in Wistar Kyoto rats that were treated with warfarin and vitamin K (warfarin inhibits matrix Gla protein (MGP) and induces calcification). The treatment was effective only when given for at least 4 weeks and not for 1 week of an 8-week treatment with warfarin and vitamin K [16]. In vitro studies with VSMCs have been conducted in search of mechanisms of the calcification process at the cellular level that can be inhibited by therapy. It is has been demonstrated that extracellular calcium alone is sufficient to accelerate matrix mineralization of VSMCs in vitro [17].

Author's personal copy Cardiovasc Drugs Ther Table 1 Human studies of the effect of antihypertensive treatment on vascular calcification

Motro et al. 2001 [40]


Calcification assessment technique


N =201 High risk hypertensive patients

Double helix coronary tomography

Nifedipine vs co-amilozide 3 years (hydrochlorothizide/ amiloride) ACE -I perindopril 3 years vs placebo

Bruining et al. 2009 [6] N =119 Patients of the PERSPECTIVE trial


Budoff et al. 2004 [7]

Coronary computed Aged garlic extract tomographic vs control angiography Coronary electron beam ACE-I or ARB computed treatment vs control tomography

N =19 patients

Maahs et al. 2006 [36] N =478 type I diabetic patients


1 year

2.5 years


Slower progression of coronary calcification in patients on nifedipine Coronary plaques with no or little calcium (0–25 %) regressed on perindopril and did not change on placebo Inhibition of progression of coronary calcification compared to controls ACE-I/ARB treatment was associated with substantially lower odds of CAC progression

ICUS Intracoronary ultrasound, ACE-I angiotensin converting enzyme inhibitors, ARB angiotensin receptor blockers, CAC coronary artery calcification

Subsequently, it can be postulated that L-type CCBs could affect osteogenic conversion and matrix mineralization of VSMCs by inhibiting calcium influx into VSMCs. It is important to note that VSMCs are the chief conductors of calcification, orchestrating the disease process. To this end, VSMCs acquire an osteogenic phenotype in response to stress stimuli and are able to secrete an osteoid-like matrix which can calcify vessels. In this transformation, secretion of calcified micro-vesicles seems to play a major role. In order to untangle the role of these micro-vesicles Chen et al. examined whether the blockade of L-type calcium channels inhibits their production and hence VC. In doing so, bovine VSMCs or rat aorta organ cultures were incubated in media known to promote calcification and treated with the L-type calcium channel inhibitors verapamil, nifedipine and nimodipine. The phenylalkylamine verapamil significantly decreased calcification of the VSMCs and rat aorta, in a dosedependent manner, whereas the dihydropyridines nifedipine and nimodipine had no effect. Verapamil pretreatment of the cells also inhibited matrix vesicle alkaline phosphatase activity and reduced the ability of these micro-vesicles to subsequently calcify on a type I collagen extracellular matrix scaffold. As L-type channels are blocked by verapamil and dihydropyridines, the authors suggested that verapamil inhibits vascular smooth muscle mineralization and matrix vesicle activity by mechanisms other than the simple blockade of this calcium channel activity. However, to what extent CCBs prevent VSMC micro-vesicle mineralization in humans is yet to be established [18]. Similarly, Trion et al. showed that calcium deposition in VSMCs (stimulated dose-dependently by b-glycerophosphate, CaCl2, and ascorbic acid) was not affected by the addition of amlodipine (0.01–1 μmol/l) to the calcification medium [19].

The most recent study to examine the effects of CCBs on VSMC calcification was published early this year and involved a new dihydropyridine, azelnidipine. This CCB is proposed to have unique anti-atherogenic properties beyond its class effects, such as more enhanced NO production in endothelial cells than other CCBs and down-regulation of gene-expression of molecular components of the reninangiotensin-aldosterone system. Azelnidipine was found to significantly decrease alkaline phosphatase and the activity of Msx-2, a key factor of VC in human aortic VSMCs, while verapamil and diltiazem had no effect [20]. Figure 1 shows the effects of antihypertensive medication on promoters and inhibitors of VC.

Angiotensin Converting Enzyme Inhibitors (ACEi) /Angiotensin Receptor Blockers (ARBs)/Aldosterone Antagonists It is now known that ACE-i, ARBs and aldosterone antagonists interfere with the renin-angiotensin-aldosterone system (RAAS) and exert beneficial actions on vascular tissue beyond their blood pressure-lowering effects [21]. The effects of ACE inhibition on coronary plaque progression in humans in relation to its calcium content have been investigated in the recent past in the PERSPECTIVE study. This was a substudy of the EUROPA trial which used intravascular ultrasound (IVUS), to test the effects of perindopril on coronary plaque. The study showed that plaques with no or little calcium (0–25 %) regressed with perindopril, but did not change with placebo. Plaques containing moderate calcium (group 25–50 %) did not change and plaques with severe amounts of calcification (group 50–100 %) equally progressed.

Author's personal copy Cardiovasc Drugs Ther Table 2 Experimental animal models studies of the effect of antihypertensive medication on vascular calcification Author, date

Experimental model


Essalihi et al. 2007 [18]

Male Wistar rats

Zhang et al. 2008 [66]

Human umbilical vein endothelial cells

Determination of calcium Warfarin and Vit K Amlodipine reversed medial elastocalcinosis content in the carotid and the or Warfarin Vit K when administered for 4 weeks aorta and amlodipine Expression of BMP-2 Irbesartan Irbesartan suppressed BMP-2 that was induced by Ang II

Armstrong et al. 2011 [3]

New Zealand white rabbits

Micro computed tomography of Olmesartan the thoracic aorta

Ng et al. 2011 [44]

Lewis polycystic kidney Micro computed tomography of Perindopril (LPK) rat model of the thoracic aorta cystic renal disease and Lewis controls Spontaneous Atomic absorption Perindopril hypertensive rats spectrophotometry

Ng et al. 2012 [43]


Salem 2012 [52]

Wistar Kyoto rats

Micro computed tomography of Magnesium the thoracic aorta

Wu et al. 2012 [64]

Adult male Sprague– Dawley rats

Arishiro et al. 2007 [2]

Male Japanese White rabbits, cholesterol fed

Calcium content of the aortas by Captopril absorption spectrophotometry Aldosterone at 422.7 nm Osteopontin levels. CD31 Olmesartan immunostaining to assess endothelial integrity.

Rahman et al. 2010 [48]

Sprague–Dawley rats

Coronary calcification by absorption spectophotometry

Furosemide Captopril Furosemide plus Captopril

Tokumoto et al. 2009 [58] Dao et al. 2002 [14]

Normal and 5/6 nephrectomized rats Wistar rats treated with warfarin and vitamin K and controls

Calcium content of the aorta

Enalapril Darusentan Irbersartan Hydrochlorothiazide

Essahili et al. 2005 [17]

Wistar rats treated with warfarin and vitamin K and controls

Calcium levels in thoracic aorta determined by colorimetry through a reaction with ocresolphthalein complex. Micro CT



Olmesartan completely inhibited calcification in the animals that were fed the atherogenic diet LPK demonstrated greater aortic calcification. This was reduced by treatment with perindopril. Calcification of the thoracic aortic segment in the SHR-treated group was 54 % lower than in untreated SHR. No difference in the abdominal aorta. When the whole aorta is considered, SHR-treated showed 48 % less calcification compared with the untreated. The increased amount of Ca2+ in the aortic rings was significantly decreased in the presence of Mg2+. Calcium deposition in vascular tissue significantly decreased with ACE-I and aldosterone receptor antagonist treatment. Olmesartan treatment was associated with a significant decrease in osteopontin. Olmesartan significantly decreased Cbfa1 mRNA expression Furosemide, either alone or in combination with captopril, prevented myocardial calcification, cardiac hypertrophy and hypertension, maintaining blood Ca2+ and phosphate levels. Enalapril alone did not suppress vascular calcification Darusentan was the most effective to regress existent aortic calcification

Darusentan caused regression of the amount of calcium in the vascular wall produced by treatment with warfarin/vitamin K

CT computed tomography, ACE-I angiotensin converting enzyme inhibitors, BMP-2 bone morphogenic protein

The authors conclude that non-calcified coronary plaques may be amenable to regression with ACE inhibition [22]. On the contrary, ACE-i or ARB treatment was associated with substantially lower odds of CAC progression in 478 young type I diabetic patients with albuminuria compared to those not treated with ACE-i or ARB over 2.5±0.4 years [23]. In experimental animal models, RAAS inhibition has shown favourable results towards lowering of VC. Specifically, Ng et al., in the Lewis polycystic kidney (LPK) rat model of cystic renal disease showed that perindopril

ameliorated medial elastocalcinosis of the thoracic aorta as well as the overall aortic compliance measured by pulse wave velocity [24]. In a more recent study the same group used spontaneously hypertensive rats (SHR) and showed that early treatment with perindopril was associated with a reduction in total aortic calcification (48 %, P 60 years of age. As mentioned, VC can occur in localized intimal plaques or in a diffuse fashion in the media. The high incidence of cardiovascular mortality in subjects with detectable CAC, is at least partially, attributable to increased medial calcification of the large arteries, which in turn results in increased wall stiffness and pulse pressure and decreased myocardial perfusion during diastole [1]. Thus, attenuating VC could be protective for the cardiovascular system. On the other hand, medial calcification which is the result of the change in smooth muscle cell phenotype to an osteochondrogenic state may be a tissue repair mechanism [73]. Teleologically, elastocalcinosis may be a mechanism that “repairs” elastic fibres damaged by cumulative systolic pressure and the long term results of disturbing this mechanism are still unknown. The second type of calcification, that is intimal calcification of the atheromatous plaque, is even more frequent than medial calcification, especially in groups with

excess cardiovascular risk [74]. A major complication of intimal calcification is plaque rupture, which leads to serious sequelae such as myocardial infarction and cerebrovascular events. Hypertension is also thought to be causal in acute plaque rupture by increasing the pulsatile mechanical stress on plaques. It is interesting that the direct contribution of calcification to plaque rupture is unclear and conflicting. Some studies suggest that calcification increases biomechanical stress on plaques rendering them prone to rupture, whilst other evidence indicated that calcification can be protective and stabilize plaques, making them less likely to rupture. Recent studies now suggest that the distribution of calcification, rather than its mere presence may predispose to plaque rupturediffuse and speckled micro-calcium deposits (termed “spotty calcification”), are associated with greater risk of plaque rupture [75]. In this context, studies on treatments targeting VC should be carefully planned in order to possibly discriminate special phenotypes that will benefit from a decrease in VC. The largest study to investigate the effect of CAC on cardiovascular events is the Multi-Ethnic Study of Atherosclerosis (MESA). In this study, CAC was found to be an independent predictor of CVD in intermediate risk individuals. CAC provided superior discrimination and risk reclassification compared to other risk markers [76]. The extent to which blood pressure lowering itself regresses VC is not yet fully elucidated. After years of research, it has now become basic knowledge that blood pressure lowering is more important than the choice of drug class in preventing cardiovascular diseases [71, 77]. Blood pressure reduction, however, possibly relieves the calcification stress through reduction of the arterial remodelling of large arterial conduits. In this way, changes in extracellular matrix composition as well as synthetic/proliferative VSMC differentiation are possibly attenuated. The attenuation of these processes will most likely not allow the calcification process to evolve [13]. To date, direct evidence of a beneficial effect for the attenuation of VC is currently lacking. More research is needed in this field to explore the potential role of antihypertensive interventions on VC and investigate whether reduction of VC leads to less cardiovascular mortality but also whether the effects of these drugs stem merely from their blood pressure reduction properties or also from their interference in the “bone-vascular axis”. Statins and anti-osteoporotic drugs have been tested for the regression of VC. The former class showed no impact in a recent meta-analysis, while the effect of the latter class, particularly the biphosphonates, lacks the necessary evidence to draw safe conclusions [78]. The same is the case for the antihypertensive agents. RAAS inhibitors and CCBs could have an impact but more studies in humans are necessary to establish this issue.

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While awaiting more studies to address this very interesting hypothesis, interventions targeting solely on regressing VC should not be yet considered in clinical practice. Finally, despite the fact that future potential targets to prevent or regress both hypertension and VC, such as metalloproteinases, osteopontin, and osteoprotegerin, seem attractive options, a remaining challenge will be specifically to target VC without affecting other biomineralization processes such as bone homeostasis.

Conflict of Interest None

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