- Email: [email protected]
Understanding and treating aortopathy in bicuspid aortic valve
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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Understanding and treating aortopathy in bicuspid aortic valve Craig S. Broberg, MD, MCRa, and Judith Therrien, MDb,n a
Knight Cardiovascular Institute, Oregon Health & Sciences University, Portland, OR Jewish General Hospital, Montreal, Quebec, Canada
b
abstra ct Bicuspid aortic valve is a simple yet common condition with surprising clinical complexity. Patients are typically found to have enlargement of the ascending aorta, either root or midascending, independent of valve function. This enlargement is perceived to be a risk of aortic dissection, and therefore, prophylactic surgery is often recommended when the aorta reaches 50–55 mm in diameter. Despite the prevalence and potential health impact, there is to date no published data on the role of medical therapy. The emerging trend, however, is to address this question through clinical research. Early trials are underway designed to address the question of potential medical therapy. This article reviews current knowledge of the condition, its potential etiology, and ongoing work to assess the role of medical therapy. & 2015 Elsevier Inc. All rights reserved.
Background Prevalence of bicuspid aortic valve (BAV) BAV resulting from a fusion of two aortic valve cusps (Fig. 1) is the most common congenital cardiac anomaly. It affects 0.6–1.5% of the population due to its 2:1 male predominance [1,2]. Diagnosis is usually made at a median age of 35 years, at the peak of their productive life [3–7]. Furthermore, the defect is inheritable, affecting 20–50% of their offspring. The prevalence of BAV is nearly 10-fold higher in first-degree relatives of BAV patients than in the general population [4], and its inheritance is observed in more than 50% of families if associated non-valvular complications are present [8].
BAV-associated aortopathy BAV is not a benign condition. The diagnosis carries a 42% rate of cardiovascular events at 20-year follow-up [1]. Aortic dilatation (Fig. 1) occurs in 50% of patients [4–6], with an The authors have indicated there are no conflicts of interest. n Corresponding author. Tel.: þ1 514 340 8222; fax: þ1 514 340 7534. E-mail address: [email protected] (J. Therrien). http://dx.doi.org/10.1016/j.tcm.2014.12.006 1050-1738/& 2015 Elsevier Inc. All rights reserved.
age-adjusted 86% increase in the relative risk of developing aortic aneurysm compared to the general population [7]. Once aortic aneurysm is present, the risk of aortic dissection increases by 14-fold [7]. Over a 25-year follow-up, 26% of patients with BAV will require aortic surgical intervention to prevent/treat thoracic aortic aneurysmal disease (TAAD) [7] (Fig. 2) at a mean age of 49 years [9]. Aortic surgery carries a 2–5% post-operative mortality [10,11] and considerable longterm morbidity, including embolic stroke, major bleeding, endocarditis, and need for reoperation [11].
Mechanism of BAV-related aortic dilatation Although the association between BAV and aortic disease is well established, the mechanism of this association is unclear and controversial. Yet, understanding the etiology is important for developing appropriate treatment options [4–6,12]. Histological studies of aortic dilation in BAV patients have demonstrated medial degeneration of the aortic wall, characterized by fragmentation and disruption of the medial
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Fig. 1 – Magnetic resonance images showing BAV with right and left coronary cusp fusion (left panel) and ascending aorta dilatation at either the root (center) or the midascending (right panel). elastic fibers [13–16] (Fig. 3, left), similar to that of Marfan disease (Fig. 3, right). Whether the aortopathy is determined by abnormal blood flow patterns in the ascending aorta from different cusp fusion patterns (see below) [17–21] or genetic variants that perhaps mediate an increase in transforming growth factor-β (TGFβ) activity (see below) [22–26] or a combination of both is a matter of considerable debate. Structural abnormalities of the aortic wall commonly accompany BAV, even when the valve is not stenotic, and this may potentiate both aortic dilation and aortic dissection. The development of the aortic and pulmonary valves is intimately linked to outflow tract septation and aorta/aortic arch development from the common arterial trunk [27]. Interactions between the second heart field and neural crest patterning are important in orchestrating the development of the outflow tract along with the aortic arch, from the common arterial trunk [27]. Neural crest cells contribute to the formation of vascular smooth muscle cells (VSMCs) of the aorta and coronary arteries and intervene in the late phase of semilunar valve development [28]. Disruption of Notch
Fig. 2 – Risk of aortic surgery after BAV diagnosis. (Adapted with permission from Michelena et al. [7].)
signaling in the second heart field of transgenic mice, by using a truncated form of a mastermind-like protein (a transcriptional co-activator of Notch), is associated with defective neural crest cells patterning and unequal aortic valve leaflets with a bicuspid-like morphology and aortic arch abnormalities typified by disorganized aortic wall histology with dispersed VSMCs. Thus, the association between BAV and aortopathy may be based on embryologic patterning of neural crest cells. Interestingly, the aorta of patients with BAV shows a high level of apoptosis in neural crest-derived cells [29]. In association with an elevated rate of apoptosis, the aorta of BAV patients shows fragmented elastic fibers with increased distance between the elastic lamellae [30]. Furthermore, dilated aortas from patients with BAV have a higher content of metalloproteinase (MMP) and a lower level of tissue inhibitor of metalloproteinase compared to tricuspid aortic valve patients, indicating an increased collagen turnover [16]. Therefore, increased collagen turnover and decreased collagen cross-linking may be a factor in aneurysm formation in patients with BAV. Hence, although not yet established firmly in humans, it is possible that one or more defects originating from the patterning of neural crest cells play a role in BAV pathophysiology. Plausible biochemical pathways leading to BAV aortopathy have been proposed (Fig. 4). Much of this is based on emerging research in Marfan syndrome, a mutation of the fibrillin-1 gene (FBN1) that results in higher signaling through the transforming growth factor beta 1 (TGFβ-1) pathway with increased phosphorylation of Smad2/3. Interestingly, BAV aortic tissues have lower fibrillin-1 content coupled with higher TGFβ-1 levels [13,31], and common non-Marfan mutations in FBN1 have been shown to be associated with TAAD in BAV patients [32]. Fibrillin-1 contributes to the elastomeric properties of the connective tissue and also has interactions with TGFβ family of proteins. Studies performed in the last several years have emphasized the concept that abnormal
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Fig. 3 – (Left) medial degeneratio n of ascending aorta in patients with BAV (Verhoeff–Van Gieson stain, original magnification 50). (Right) medial degeneration of the ascending aorta in Marfan patients. secretion of fibrillin-1 leads to activation of TGFβ-1 by freeing it from microfibril-bound large latent complex [33]. Favoring a genetic etiology, recent studies have shown increased TGFβ activity in the wall of BAV aortopathy with an intrinsic and unique defect in TGFβ1 receptor expression [34], which together are responsible for an increase in matrix cell degradation, elastic fiber degeneration, and aneurysm formation [14]. These promising findings have fueled the development of several randomized trials to evaluate the effect of losartan upon aortic morbidity and mortality in patients with Marfan syndrome [35]. Whether similar mechanisms can be transposed to BAV-associated aortopathy is unknown. A key observation in BAV-associated aortopathy is the asymmetrical pattern of histological abnormalities, which is also linked to the expression of genes involved in tissue remodeling. Several studies have shown that elastic fiber fragmentation and apoptosis of VSMCs were mostly observed at the convexity of the aorta but were attenuated at the concavity of the aorta [36]. In addition, expression of collagen types I and III was reduced in the convexity when compared to the concavity [15]. Of particular importance, the opening of BAV is asymmetrical and alters flow, which gives rise to an uneven wall stress distribution in the aorta. The right (R)–left (L) type of fusion has been associated with a right anterior jet, whereas R–N (non-coronary) fusion is related to an abnormal and eccentric left posterior jet. The specific flow patterns of different cusp configurations may explain the observation that R–L fusion is associated with a right anterior jet and more frequent asymmetrical enlargement of aorta at the convexity, whereas the R–N fusion is sometimes associated with more frequent enlargement of the tubular aorta with extension into the aortic arch [21,37,38]. R–N cusp fusion results in a more central or left posterior blood flow jet that is associated with a lower risk of aortic aneurysm [37,38]. Hence, considering the non-homogeneous distribution of biomolecular changes within the BAV aorta, it is possible that hemodynamic factors like eccentric shear wall stress may contribute along with the genotype to the development of different phenotypes associated with BAV and accelerated medial aortic wall degeneration. Thus, tenable hypotheses for the markedly increased incidence and severity of early-onset TAAD seen in BAV patients include (i) abnormal mechanical strain and flow patterns across the BAV that initiate or cause ascending aortic dilation
or; (ii) genetically altered cellular substrate of BAV that favors TAAD, independent of the hemodynamic forces; or (iii) a combination of mechanical stress with pre-existing genetic variation, which contributes to specific spatial alteration of extracellular matrix in BAV [32–34]. The 2014 ACC/AHA guidelines for thoracic aortic disease provide a Class I indication to fully image the aorta with echocardiography, CT, or magnetic resonance imaging in individuals with BAV, in order to detect TAAD [39], since early identification and careful surveillance of individuals with BAV remain the primary clinical strategies. Yearly echocardiography (or CT or MRI if the ascending aorta is not well visualized) in these patients is recommended once the aorta reaches 45 mm. It is possible that genetic risk markers may augment the prediction of TAAD in patients with BAV and may reduce imaging needs and costs in the near future. Although existing data provide clues as to the biochemical pathways leading to dilatation (Fig. 4), they do not as yet prove the involvement of any specific enzymatic reactions in BAV specifically. For example, matrix metalloproteineases (MMPs) have been implicated as being crucial in the final common pathways of dilatation, leading to features such as
Fig. 4 – Potential molecular mechanisms for aortic aneurysm formation and targets for medical therapy options. ARB ¼ angiotensin receptor blockade. (Adapted with permission from Danyi et al. Medical therapy of thoracic aortic aneurysms: are we there yet? Circulation 2011; 124:1469–1476.)
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VSMC apoptosis and cystic medial necrosis, although data are mixed. MMP isoform 9 expression in aneurysmal BAV aortic tissue has been shown [14,40]. Yet several other investigations did not find meaningful differences in the plasma expression, mRNA, or allelic makeup of MMP in affected individuals [41–44].
Treatment for BAV-related aortic dilatation In atherosclerotic aortas, the risk of aortic dissection and rupture increases exponentially with aortic dimension [45], with a 4.3-fold increased risk of rupture or dissection in an aneurysm 60–69 mm in diameter compared to an aneurysm 40–49 mm in diameter (Fig. 5) [46]. In BAV aortopathy, once aortic aneurysm is present, the risk of aortic dissection increases by 14-fold [7]. Aortic root surgery is recommended when the aorta reaches 50–55 mm, because it is the only treatment available [39,47–49]. Proven medical intervention in patients with BAV aortopathy aimed at preventing or stabilizing aortic enlargement before it reaches 50–55 mm does not exist. A more sedentary lifestyle and avoidance of heavy weight lifting is the only prophylactic measure suggested to curtail further aortic dilatation [48]. There is some retrospective evidence suggesting a role of HMG CoA reductase inhibitors (statins) in preventing aortopathy in BAV [56], but this remains to be proven in a prospective fashion [50]. Currently, there are as yet no known medical therapies that can alter the progression of aortic root dilatation.
Treatment of Marfan aortopathy Studies in patients with Marfan syndrome and ascending aortopathy suggest that β-blockers (BB), which cause decrease in wall shear stress, may reduce the rate of aortic dilatation [51,52]. More recently, angiotensin receptor blockers (ARB), through their direct and indirect inhibition of TGFβ, have been shown to reverse aortic root dilatation in mice with analogs of Marfan syndrome [53,54] and delay aortic dilatation in humans [55]. Lastly, a recent study of an ARB (Losartan) in addition to a BB showed a 50% reduction (1.55 vs. 0.77 mm over 3 years) in the rate of progression of aortic root dilatation in patients with Marfan syndrome [56]. Six more trials of ARBs vs. BB in Marfan syndrome are underway and will be reported
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between 2014 and 2017. Of note, none of these studies are powered to look at changes in the clinical outcome (i.e., aortic dissection), as it would necessitate a large number of patients being followed up for a long time. Rather, the primary outcome of all Marfan trials has always been one of progression of aortic root dilatation [35,51,52,55,56]. Considering the similarities in the histopathology of the aorta and the natural history of patients with Marfan and BAV aortopathy, as well as the mechanism of BAV aortopathy (eccentric shear stress with or without a genetic abnormality), it is possible that BB, through a decrease in shear stress, or ARB, through a decrease in TGFβ-1 activity, could also be beneficial in BAV patients with aortopathy. However, direct comparisons with Marfan syndrome and extrapolation of data are not easily justified [18]. Aortic dilatation may be the only characteristic these populations share. BAV patients have none of the other connective tissue characteristics seen in Marfan syndrome. Marfan patients likewise have no inherent valve dysfunction producing abnormal shear. Importantly, even the phenotype of aortic enlargement differs. BAV patients often dilate the midproximal aorta more so than the root, in difference to root dilatation in Marfan syndrome. Thus recognizing that BAV and Marfan are separate entities, one cannot empirically assume that BB and/or ARB will work in a similar fashion.
Ongoing BAV Registry Lack of data has not kept providers from making recommendations to patients. Considering what is at stake, empiric treatment with commonly used medications is not surprising. From the NIH-funded GenTAC registry on familial aortopathy [57], we identified 180 BAV patients with no known indication for BB or ARB/ACEi treatment. Of these, 35% were taking BB, 16% were using an ARB, and 16% were using an ACEi. Drug use was highest among those with aortic dilatation. Patients on BB were significantly older than those not on the drug (40.1 7 19.5 vs. 25.9 7 19.6 years, p o 0.001), while there was no difference in the age of those on ARB or ACEi. Furthermore, there was significant inter-institutional variation in prescribing BB. The percentage of patients taking BB ranged from 26% to 71% (p ¼ 0.02). Less variation was seen with ARB or ACEi use. Consensus guidelines are generally supportive of empiric therapy with antihypertensive medication, despite the lack of data. The ACC/AHA guidelines for treatment of adult congenital heart disease list BB in BAV as a class IIa recommendation, level of evidence C (class I in Marfan syndrome) [58]. This mirrors the valvular heart disease guidelines stating BB treatment is reasonable when the aorta reaches 40 mm [39]. The thoracic aortic guidelines state that use of these medications is reasonable “to the lowest point patients can tolerate without adverse effects” [59]. Given such statements, the usage data from GenTAC reported above may be viewed as too low. Data are needed to refine and legitimize these recommendations.
Ongoing BAV aortopathy trials
Fig. 5 – The relationship between aortic size and dissection. (Adapted with permission from Coady et al. [46].)
To our knowledge, two studies are currently being conducted to finally end the data eclipse on the subject of BAV aortopathy.
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US clinical trial feasibility study (NCT01920815) A feasibility study of a comparative effectiveness study is now underway. The study is a multicenter prospective project that primarily aims to gather initial experience on screening, enrollment, and existing medical therapy of a BAV population. The study to date has screened over 1800 patients, roughly half of who have an enlarged aorta (defined as any diameter reported 43.5 cm). Eligible patients are being followed up prospectively in an observational study (no intervention) with a limited subset entered into an imaging arm to undergo MRI at baseline and in 2 years. The MRI protocol is designed to maximize consistency in plane alignment between baseline and follow-up and will determine the most robust metric to follow. The study is intended to inform the design of a robust clinical trial based on eligibility data, variance of the intended end point, and number needed to screen at tertiary care centers with community partnership.
Canadian study (NCT01202721) A pan-Canadian pilot study looking at the effect of Telmisartan (ARB) or Atenolol (BB) on aortic dilatation is currently underway in adult patients with BAV and ascending aortopathy (aorta 437 mm). The primary end point is the rate of aortic dilatation based on MRI performed at baseline and 5 years. Assuming a rate of progression of ascending aorta dilatation of 0.5 mm per year [6,60,61], a 25% reduction in the rate of progression in patients on active medication (ARB or BB), and a 20% rate of loss to follow-up, the calculated sample size is 420 patients for a power of 80% and significance level of 0.05. The study has randomized 102 patients with BAV and associated aortopathy with a mean follow-up of 8.4 months. There has been no loss to follow-up so far, and patients have tolerated the medications very well. Plans to expand the study to the United States and Europe are underway.
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BAV is a common congenital disorder, with associated aortopathy being present in 50% of the cases. The etiology of aneurysm formation is likely a combination of increased wall shear stress from an eccentric flow in the aorta (hemodynamic hypothesis), compounded by the increase in TGFβ activity (genetic hypothesis). The value of medical therapy remains uncertain, but studies are underway to address this issue. A proper study will have the potential of affecting literally millions of individuals given the large number of patients with BAV and the prevalence of aortic enlargement. Avoidance of either catastrophic aortic dissection or surgical aortoplasty with its inherent risk, life disruption, and cost would have tremendous value for these individuals.
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The common use of medical therapy already in use demonstrates caregivers hope to avoid these complications through the use of pharmacotherapy. At the same time, documentation of an absence of effect of one therapy or another, or significant pragmatic roadblocks to compliance, may help avoid unnecessary prescribing of ineffective therapy. Thus, newly emerging clinical studies addressing the potential for medical therapy in BAV aortopathy would have a tremendous potential impact worldwide.
Future research directions and considerations of clinical trials A role for combination therapy with ARB and BB could be proposed, given complimentary methods of action, but should be addressed in other studies. Similarly, the potential use of statin drugs likely deserves secondary study.
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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Understanding and treating aortopathy in bicuspid aortic valve Craig S. Broberg, MD, MCRa, and Judith Therrien, MDb,n a
Knight Cardiovascular Institute, Oregon Health & Sciences University, Portland, OR Jewish General Hospital, Montreal, Quebec, Canada
b
abstra ct Bicuspid aortic valve is a simple yet common condition with surprising clinical complexity. Patients are typically found to have enlargement of the ascending aorta, either root or midascending, independent of valve function. This enlargement is perceived to be a risk of aortic dissection, and therefore, prophylactic surgery is often recommended when the aorta reaches 50–55 mm in diameter. Despite the prevalence and potential health impact, there is to date no published data on the role of medical therapy. The emerging trend, however, is to address this question through clinical research. Early trials are underway designed to address the question of potential medical therapy. This article reviews current knowledge of the condition, its potential etiology, and ongoing work to assess the role of medical therapy. & 2015 Elsevier Inc. All rights reserved.
Background Prevalence of bicuspid aortic valve (BAV) BAV resulting from a fusion of two aortic valve cusps (Fig. 1) is the most common congenital cardiac anomaly. It affects 0.6–1.5% of the population due to its 2:1 male predominance [1,2]. Diagnosis is usually made at a median age of 35 years, at the peak of their productive life [3–7]. Furthermore, the defect is inheritable, affecting 20–50% of their offspring. The prevalence of BAV is nearly 10-fold higher in first-degree relatives of BAV patients than in the general population [4], and its inheritance is observed in more than 50% of families if associated non-valvular complications are present [8].
BAV-associated aortopathy BAV is not a benign condition. The diagnosis carries a 42% rate of cardiovascular events at 20-year follow-up [1]. Aortic dilatation (Fig. 1) occurs in 50% of patients [4–6], with an The authors have indicated there are no conflicts of interest. n Corresponding author. Tel.: þ1 514 340 8222; fax: þ1 514 340 7534. E-mail address: [email protected] (J. Therrien). http://dx.doi.org/10.1016/j.tcm.2014.12.006 1050-1738/& 2015 Elsevier Inc. All rights reserved.
age-adjusted 86% increase in the relative risk of developing aortic aneurysm compared to the general population [7]. Once aortic aneurysm is present, the risk of aortic dissection increases by 14-fold [7]. Over a 25-year follow-up, 26% of patients with BAV will require aortic surgical intervention to prevent/treat thoracic aortic aneurysmal disease (TAAD) [7] (Fig. 2) at a mean age of 49 years [9]. Aortic surgery carries a 2–5% post-operative mortality [10,11] and considerable longterm morbidity, including embolic stroke, major bleeding, endocarditis, and need for reoperation [11].
Mechanism of BAV-related aortic dilatation Although the association between BAV and aortic disease is well established, the mechanism of this association is unclear and controversial. Yet, understanding the etiology is important for developing appropriate treatment options [4–6,12]. Histological studies of aortic dilation in BAV patients have demonstrated medial degeneration of the aortic wall, characterized by fragmentation and disruption of the medial
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Fig. 1 – Magnetic resonance images showing BAV with right and left coronary cusp fusion (left panel) and ascending aorta dilatation at either the root (center) or the midascending (right panel). elastic fibers [13–16] (Fig. 3, left), similar to that of Marfan disease (Fig. 3, right). Whether the aortopathy is determined by abnormal blood flow patterns in the ascending aorta from different cusp fusion patterns (see below) [17–21] or genetic variants that perhaps mediate an increase in transforming growth factor-β (TGFβ) activity (see below) [22–26] or a combination of both is a matter of considerable debate. Structural abnormalities of the aortic wall commonly accompany BAV, even when the valve is not stenotic, and this may potentiate both aortic dilation and aortic dissection. The development of the aortic and pulmonary valves is intimately linked to outflow tract septation and aorta/aortic arch development from the common arterial trunk [27]. Interactions between the second heart field and neural crest patterning are important in orchestrating the development of the outflow tract along with the aortic arch, from the common arterial trunk [27]. Neural crest cells contribute to the formation of vascular smooth muscle cells (VSMCs) of the aorta and coronary arteries and intervene in the late phase of semilunar valve development [28]. Disruption of Notch
Fig. 2 – Risk of aortic surgery after BAV diagnosis. (Adapted with permission from Michelena et al. [7].)
signaling in the second heart field of transgenic mice, by using a truncated form of a mastermind-like protein (a transcriptional co-activator of Notch), is associated with defective neural crest cells patterning and unequal aortic valve leaflets with a bicuspid-like morphology and aortic arch abnormalities typified by disorganized aortic wall histology with dispersed VSMCs. Thus, the association between BAV and aortopathy may be based on embryologic patterning of neural crest cells. Interestingly, the aorta of patients with BAV shows a high level of apoptosis in neural crest-derived cells [29]. In association with an elevated rate of apoptosis, the aorta of BAV patients shows fragmented elastic fibers with increased distance between the elastic lamellae [30]. Furthermore, dilated aortas from patients with BAV have a higher content of metalloproteinase (MMP) and a lower level of tissue inhibitor of metalloproteinase compared to tricuspid aortic valve patients, indicating an increased collagen turnover [16]. Therefore, increased collagen turnover and decreased collagen cross-linking may be a factor in aneurysm formation in patients with BAV. Hence, although not yet established firmly in humans, it is possible that one or more defects originating from the patterning of neural crest cells play a role in BAV pathophysiology. Plausible biochemical pathways leading to BAV aortopathy have been proposed (Fig. 4). Much of this is based on emerging research in Marfan syndrome, a mutation of the fibrillin-1 gene (FBN1) that results in higher signaling through the transforming growth factor beta 1 (TGFβ-1) pathway with increased phosphorylation of Smad2/3. Interestingly, BAV aortic tissues have lower fibrillin-1 content coupled with higher TGFβ-1 levels [13,31], and common non-Marfan mutations in FBN1 have been shown to be associated with TAAD in BAV patients [32]. Fibrillin-1 contributes to the elastomeric properties of the connective tissue and also has interactions with TGFβ family of proteins. Studies performed in the last several years have emphasized the concept that abnormal
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Fig. 3 – (Left) medial degeneratio n of ascending aorta in patients with BAV (Verhoeff–Van Gieson stain, original magnification 50). (Right) medial degeneration of the ascending aorta in Marfan patients. secretion of fibrillin-1 leads to activation of TGFβ-1 by freeing it from microfibril-bound large latent complex [33]. Favoring a genetic etiology, recent studies have shown increased TGFβ activity in the wall of BAV aortopathy with an intrinsic and unique defect in TGFβ1 receptor expression [34], which together are responsible for an increase in matrix cell degradation, elastic fiber degeneration, and aneurysm formation [14]. These promising findings have fueled the development of several randomized trials to evaluate the effect of losartan upon aortic morbidity and mortality in patients with Marfan syndrome [35]. Whether similar mechanisms can be transposed to BAV-associated aortopathy is unknown. A key observation in BAV-associated aortopathy is the asymmetrical pattern of histological abnormalities, which is also linked to the expression of genes involved in tissue remodeling. Several studies have shown that elastic fiber fragmentation and apoptosis of VSMCs were mostly observed at the convexity of the aorta but were attenuated at the concavity of the aorta [36]. In addition, expression of collagen types I and III was reduced in the convexity when compared to the concavity [15]. Of particular importance, the opening of BAV is asymmetrical and alters flow, which gives rise to an uneven wall stress distribution in the aorta. The right (R)–left (L) type of fusion has been associated with a right anterior jet, whereas R–N (non-coronary) fusion is related to an abnormal and eccentric left posterior jet. The specific flow patterns of different cusp configurations may explain the observation that R–L fusion is associated with a right anterior jet and more frequent asymmetrical enlargement of aorta at the convexity, whereas the R–N fusion is sometimes associated with more frequent enlargement of the tubular aorta with extension into the aortic arch [21,37,38]. R–N cusp fusion results in a more central or left posterior blood flow jet that is associated with a lower risk of aortic aneurysm [37,38]. Hence, considering the non-homogeneous distribution of biomolecular changes within the BAV aorta, it is possible that hemodynamic factors like eccentric shear wall stress may contribute along with the genotype to the development of different phenotypes associated with BAV and accelerated medial aortic wall degeneration. Thus, tenable hypotheses for the markedly increased incidence and severity of early-onset TAAD seen in BAV patients include (i) abnormal mechanical strain and flow patterns across the BAV that initiate or cause ascending aortic dilation
or; (ii) genetically altered cellular substrate of BAV that favors TAAD, independent of the hemodynamic forces; or (iii) a combination of mechanical stress with pre-existing genetic variation, which contributes to specific spatial alteration of extracellular matrix in BAV [32–34]. The 2014 ACC/AHA guidelines for thoracic aortic disease provide a Class I indication to fully image the aorta with echocardiography, CT, or magnetic resonance imaging in individuals with BAV, in order to detect TAAD [39], since early identification and careful surveillance of individuals with BAV remain the primary clinical strategies. Yearly echocardiography (or CT or MRI if the ascending aorta is not well visualized) in these patients is recommended once the aorta reaches 45 mm. It is possible that genetic risk markers may augment the prediction of TAAD in patients with BAV and may reduce imaging needs and costs in the near future. Although existing data provide clues as to the biochemical pathways leading to dilatation (Fig. 4), they do not as yet prove the involvement of any specific enzymatic reactions in BAV specifically. For example, matrix metalloproteineases (MMPs) have been implicated as being crucial in the final common pathways of dilatation, leading to features such as
Fig. 4 – Potential molecular mechanisms for aortic aneurysm formation and targets for medical therapy options. ARB ¼ angiotensin receptor blockade. (Adapted with permission from Danyi et al. Medical therapy of thoracic aortic aneurysms: are we there yet? Circulation 2011; 124:1469–1476.)
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VSMC apoptosis and cystic medial necrosis, although data are mixed. MMP isoform 9 expression in aneurysmal BAV aortic tissue has been shown [14,40]. Yet several other investigations did not find meaningful differences in the plasma expression, mRNA, or allelic makeup of MMP in affected individuals [41–44].
Treatment for BAV-related aortic dilatation In atherosclerotic aortas, the risk of aortic dissection and rupture increases exponentially with aortic dimension [45], with a 4.3-fold increased risk of rupture or dissection in an aneurysm 60–69 mm in diameter compared to an aneurysm 40–49 mm in diameter (Fig. 5) [46]. In BAV aortopathy, once aortic aneurysm is present, the risk of aortic dissection increases by 14-fold [7]. Aortic root surgery is recommended when the aorta reaches 50–55 mm, because it is the only treatment available [39,47–49]. Proven medical intervention in patients with BAV aortopathy aimed at preventing or stabilizing aortic enlargement before it reaches 50–55 mm does not exist. A more sedentary lifestyle and avoidance of heavy weight lifting is the only prophylactic measure suggested to curtail further aortic dilatation [48]. There is some retrospective evidence suggesting a role of HMG CoA reductase inhibitors (statins) in preventing aortopathy in BAV [56], but this remains to be proven in a prospective fashion [50]. Currently, there are as yet no known medical therapies that can alter the progression of aortic root dilatation.
Treatment of Marfan aortopathy Studies in patients with Marfan syndrome and ascending aortopathy suggest that β-blockers (BB), which cause decrease in wall shear stress, may reduce the rate of aortic dilatation [51,52]. More recently, angiotensin receptor blockers (ARB), through their direct and indirect inhibition of TGFβ, have been shown to reverse aortic root dilatation in mice with analogs of Marfan syndrome [53,54] and delay aortic dilatation in humans [55]. Lastly, a recent study of an ARB (Losartan) in addition to a BB showed a 50% reduction (1.55 vs. 0.77 mm over 3 years) in the rate of progression of aortic root dilatation in patients with Marfan syndrome [56]. Six more trials of ARBs vs. BB in Marfan syndrome are underway and will be reported
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between 2014 and 2017. Of note, none of these studies are powered to look at changes in the clinical outcome (i.e., aortic dissection), as it would necessitate a large number of patients being followed up for a long time. Rather, the primary outcome of all Marfan trials has always been one of progression of aortic root dilatation [35,51,52,55,56]. Considering the similarities in the histopathology of the aorta and the natural history of patients with Marfan and BAV aortopathy, as well as the mechanism of BAV aortopathy (eccentric shear stress with or without a genetic abnormality), it is possible that BB, through a decrease in shear stress, or ARB, through a decrease in TGFβ-1 activity, could also be beneficial in BAV patients with aortopathy. However, direct comparisons with Marfan syndrome and extrapolation of data are not easily justified [18]. Aortic dilatation may be the only characteristic these populations share. BAV patients have none of the other connective tissue characteristics seen in Marfan syndrome. Marfan patients likewise have no inherent valve dysfunction producing abnormal shear. Importantly, even the phenotype of aortic enlargement differs. BAV patients often dilate the midproximal aorta more so than the root, in difference to root dilatation in Marfan syndrome. Thus recognizing that BAV and Marfan are separate entities, one cannot empirically assume that BB and/or ARB will work in a similar fashion.
Ongoing BAV Registry Lack of data has not kept providers from making recommendations to patients. Considering what is at stake, empiric treatment with commonly used medications is not surprising. From the NIH-funded GenTAC registry on familial aortopathy [57], we identified 180 BAV patients with no known indication for BB or ARB/ACEi treatment. Of these, 35% were taking BB, 16% were using an ARB, and 16% were using an ACEi. Drug use was highest among those with aortic dilatation. Patients on BB were significantly older than those not on the drug (40.1 7 19.5 vs. 25.9 7 19.6 years, p o 0.001), while there was no difference in the age of those on ARB or ACEi. Furthermore, there was significant inter-institutional variation in prescribing BB. The percentage of patients taking BB ranged from 26% to 71% (p ¼ 0.02). Less variation was seen with ARB or ACEi use. Consensus guidelines are generally supportive of empiric therapy with antihypertensive medication, despite the lack of data. The ACC/AHA guidelines for treatment of adult congenital heart disease list BB in BAV as a class IIa recommendation, level of evidence C (class I in Marfan syndrome) [58]. This mirrors the valvular heart disease guidelines stating BB treatment is reasonable when the aorta reaches 40 mm [39]. The thoracic aortic guidelines state that use of these medications is reasonable “to the lowest point patients can tolerate without adverse effects” [59]. Given such statements, the usage data from GenTAC reported above may be viewed as too low. Data are needed to refine and legitimize these recommendations.
Ongoing BAV aortopathy trials
Fig. 5 – The relationship between aortic size and dissection. (Adapted with permission from Coady et al. [46].)
To our knowledge, two studies are currently being conducted to finally end the data eclipse on the subject of BAV aortopathy.
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US clinical trial feasibility study (NCT01920815) A feasibility study of a comparative effectiveness study is now underway. The study is a multicenter prospective project that primarily aims to gather initial experience on screening, enrollment, and existing medical therapy of a BAV population. The study to date has screened over 1800 patients, roughly half of who have an enlarged aorta (defined as any diameter reported 43.5 cm). Eligible patients are being followed up prospectively in an observational study (no intervention) with a limited subset entered into an imaging arm to undergo MRI at baseline and in 2 years. The MRI protocol is designed to maximize consistency in plane alignment between baseline and follow-up and will determine the most robust metric to follow. The study is intended to inform the design of a robust clinical trial based on eligibility data, variance of the intended end point, and number needed to screen at tertiary care centers with community partnership.
Canadian study (NCT01202721) A pan-Canadian pilot study looking at the effect of Telmisartan (ARB) or Atenolol (BB) on aortic dilatation is currently underway in adult patients with BAV and ascending aortopathy (aorta 437 mm). The primary end point is the rate of aortic dilatation based on MRI performed at baseline and 5 years. Assuming a rate of progression of ascending aorta dilatation of 0.5 mm per year [6,60,61], a 25% reduction in the rate of progression in patients on active medication (ARB or BB), and a 20% rate of loss to follow-up, the calculated sample size is 420 patients for a power of 80% and significance level of 0.05. The study has randomized 102 patients with BAV and associated aortopathy with a mean follow-up of 8.4 months. There has been no loss to follow-up so far, and patients have tolerated the medications very well. Plans to expand the study to the United States and Europe are underway.
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Conclusions [12]
BAV is a common congenital disorder, with associated aortopathy being present in 50% of the cases. The etiology of aneurysm formation is likely a combination of increased wall shear stress from an eccentric flow in the aorta (hemodynamic hypothesis), compounded by the increase in TGFβ activity (genetic hypothesis). The value of medical therapy remains uncertain, but studies are underway to address this issue. A proper study will have the potential of affecting literally millions of individuals given the large number of patients with BAV and the prevalence of aortic enlargement. Avoidance of either catastrophic aortic dissection or surgical aortoplasty with its inherent risk, life disruption, and cost would have tremendous value for these individuals.
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The common use of medical therapy already in use demonstrates caregivers hope to avoid these complications through the use of pharmacotherapy. At the same time, documentation of an absence of effect of one therapy or another, or significant pragmatic roadblocks to compliance, may help avoid unnecessary prescribing of ineffective therapy. Thus, newly emerging clinical studies addressing the potential for medical therapy in BAV aortopathy would have a tremendous potential impact worldwide.
Future research directions and considerations of clinical trials A role for combination therapy with ARB and BB could be proposed, given complimentary methods of action, but should be addressed in other studies. Similarly, the potential use of statin drugs likely deserves secondary study.
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