Review Article

Why Does the Bicuspid Aortic Valve Keep Eluding Us? Shinobu Itagaki, MD,* Yuting Chiang, BA,* and Gilbert H.L. Tang, MD, MSc, MBA†

Abstract: The bicuspid aortic valve (BAV) is, by far, the most common congenital cardiovascular defect encountered by cardiovascular specialists. In the United States, the number of subjects alive is estimated to be 3 million, with an approximate 1% prevalence, more than 10 times higher than the second most common congenital lesion, ventricular septal defect. BAV is subjected to early degeneration and valve dysfunction, requiring surgical intervention in the course of a lifetime for most patients. BAV is also associated with ascending aortic dilatation, also known as BAV aortopathy. Surgical indications for a dysfunctional BAV are relatively straightforward and well established; the same as those for tricuspid aortic valve (TAV), usually triggered by symptoms or ventricular dysfunction. On the other hand, while sharing the same ultimate goal of preventing life-threatening consequences, such as aortic dissection and rupture, surgical thresholds for a dilated ascending aorta are different in the setting of BAV versus TAV; generally lower in BAV. Recently, the incidence of aortic dissection was reported to be much lower than believed, and the idea of more aggressive preemptive intervention on BAV aortopathy has become controversial. Instead, the importance of a more individualized approach is being highlighted. This article will provide a comprehensive review of (1) the typical clinical course of patients with BAV under contemporary management, (2) new risk-stratifying parameters proposed to make an individualized approach possible, and (3) practical challenges all cardiovascular specialists need to know when implementing and interpreting future BAV-related studies. Key Words: bicuspid aortic valve, aortopathy, surgical indications (Cardiology in Review 2016;24: 119–130)

I

t would be simplistic to begin this review with “bicuspid aortic valve (BAV) is the most common cardiac anomaly…,” which is used as an opening sentence in most of the BAV-related literature. The prevalence of about 1 out of 100 in the general population indeed seems prevalent, but not many cardiovascular specialists understand well what the significance of this 1% prevalence means and its potential impact on their clinical practice.1 BAV is more frequently seen in cardiovascular medicine than the natural prevalence and is subjected to early degeneration and subsequent valve dysfunction, requiring surgical intervention sooner or later in the course of most patients’ lifetime. BAV is also associated with ascending aortic dilatation, also known as BAV aortopathy. Surgical indications for severely stenotic or regurgitant BAV are well defined and not different from the tricuspid aortic valve (TAV), usually triggered by symptoms or ventricular dysfunction.2,3 On the

From the *Department of Cardiothoracic Surgery, Mount Sinai Medical Center, NY; and †Section of Cardiothoracic Surgery, Department of Surgery, Westchester Medical Center, NY. Disclosure: The authors have no conflicts of interest to report. Correspondence: Gilbert H.L. Tang, Section of Cardiothoracic Surgery, Department of Surgery, Westchester Medical Center, 100 Woods Rd, Macy 114W, Valhalla, NY 10595. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1061-537724/16/2403-0119 DOI: 10.1097/CRD.0000000000000053

Cardiology in Review  •  Volume 24, Number 3, May/June 2016

other hand, although the reason to intervene on the dilated aorta is the same in BAV or TAV, primarily to prevent life-threatening or fatal consequences, namely aortic dissection or rupture, the threshold for intervention is generally set lower in BAV because of associated aortopathy. However, the preemptive nature of aortic intervention and the unclear mechanisms of BAV aortopathy make the management of BAV aortopathy still elusive and controversial. Previous US and current European guidelines lowered the surgical trigger by 5–10 mm in patients with BAV (Table 1),3–6 supported more by expert consensus than robust clinical trials. The most recent 2014 US valve guideline resets the intervention cut-off of the BAV aorta back to the pre-2006 level, reflecting the uncertainty on this subject.2 This article will focus mainly on the following three points of BAV and discuss the most current evidence-based management of BAV aortopathy: (1) the clinical course of patients with BAV under contemporary management; (2) an individualized approach to BAV aortopathy; (3) challenges in the interpretation of BAV aortopathy-related literature.

EPIDEMIOLOGY AND PATHOLOGY OF BAV The important but less or least controversial facts about BAV are listed here as a reference point before discussing the more controversial areas. First and foremost, BAV is a frequently encountered medical condition. It is, by far, the most common congenital cardiovascular defect, with an incidence of 1.37% according to the latest statistics.7 The male to female ratio is generally reported about 2 to 1. BAV seems to be inherited with an autosomal dominant pattern with variable penetrance.8–10 In the United States, the prevalence of subjects alive is estimated to be about 1% = 3 million/300 million (2 million in adults and 1 million in children), more than 10 times higher than ventricular septal defect, the second most common congenital heart defect (200,000/300 million estimated prevalence).7 Due to its earlier and more rapid degeneration, BAV accounts for almost half of the underlying causes for isolated aortic valve replacement (AVR),11 which is the second most common heart operation after coronary artery bypass grafting. Therefore, BAV has a much higher likelihood of attracting medical attention than what one might expect with the “1% prevalence.” In terms of BAV morphology, there are 3 types based on the location of cusp fusion, with right and left fusion (RL type) the most common, accounting for 60–80%; right and noncoronary cusp fusion (RN type) accounts for the most of the rest (20–40%); and the left and noncoronary fusion (LN type) is very rare, often even excluded from studies or incorporated into the RN type. Valve dysfunction in patients with BAV often begins earlier in life, initially with some degree of either aortic stenosis (AS) or aortic regurgitation (AR), but by the time the valve requires surgical intervention, AS becomes the primary dysfunction.12–14 The timing and indication of intervention on the AV are not different between BAV and TAV in the current guidelines.2,3 Patients with BAV are more likely to have dilated ascending aorta than TAV at the level of the sinus of Valsalva (root) and/or the ascending aorta (mid portion). This can be the case even in the absence of severe valve dysfunction.15 Typically, the ascending aorta is more affected than the aortic root. www.cardiologyinreview.com  |  119

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Cardiology in Review  •  Volume 24, Number 3, May/June 2016

TABLE 1.  The Trend of US and European Guidelines for the Indication of Intervention on the Ascending Aorta, Either Isolated or Concomitant with Aortic Valve Replacement Bicuspid Aortic Valve Isolated Aortic (mm) 1998 ACC/AHA valve 2006 ACC/AHA valve6 2010 US aortic5 2013 US STS aorta and valve4 2012 European valve3 2014 ACC/AHA valve2

Class: Level*

55

Concomitant with AVR (mm)

Tricuspid Aortic Valve Class:Level

50

Isolated Aortic (mm)

Class:Level

Concomitant with AVR (mm)

55

50 50

I:C I:C I:B

50

I:C

45

I:C

55

40–50 50, 45 if risk factors 55, 50 if risk factors 55, 50 if risk factors

I:C I:B

45 45

I:C I:B

55 55

I:C I:B

45 45

IIa:C, IIa:C

45

55

IIa:C

I:B, IIa:C

45

45–55 depending on risk factors 45

IIa:C

Class: Level

55

*Class of recommendation and level of evidence. ACC/AHA indicates American College of Cardiology/American Heart Association; AVR, aortic valve replacement/repair; STS, Society of Thoracic Surgeons; TAV, tricuspid aortic valve.

CLINICAL COURSE OF BAV PATIENTS UNDER CONTEMPORARY MANAGEMENT Since the previous 2006 US valve guidelines,6 several important observational studies have been reported and give us a better understanding about the clinical course of BAV disease. Here, we review the landmark studies published after the 2006 US guidelines and provide the typical BAV clinical course under contemporary management.

How Well Are We Doing on BAV Management in the Real World? In 2008 and 2011, the Mayo Clinic published landmark studies that changed the general concept of the natural history of patients with BAV (the 2008 study is a subgroup of 2011).16,17 What is novel in these studies compared with the other historical papers, which were mainly based on tertiary referral or necropsy, is that they are population-based studies dealing with residents in a geographically defined region with medical access almost solely on a single institution, which provided all cardiovascular consults and echocardiography. Although there may still be unrecognized patients with BAV, this study is the one closest to the natural history of patients with BAV in the real world under medical treatment, which was thought to be the standard during the study period (1980–1999). The 2011 Mayo Clinic study enrolled 416 consecutive echocardiographically diagnosed patients with BAV (mean age 35 years and 70% male); about 1% of all echocardiograms were performed in the institution during the study period, consistent with the wellknown “1% prevalence.”16 Unlike other studies, at study enrollment most of the patients were still free of severe valve disease or aortic aneurysm, with only 23% having mild or worse stenosis (transvalvular gradient > 20 mmHg), 59% having some degree of regurgitation, and only 8% with aortic aneurysm (diameter > 45 mm). With a mean follow-up of 15 years (maximum up to 25 years), the incidence of late mortality, AVR, aortic surgery, new aortic aneurysm formation, and aortic dissection was investigated. Simply put, the study showed how patients with BAV who were detected early, e.g., in their 30s, are faring until 60 years old under standard medical surveillance and subsequent surgical intervention as needed. As the authors pointed out, this study gave us both reassurance and concern. The reassuring findings were that the 25-year survival of patients with BAV is 80%, equivalent to the age- and sex-matched general population, and aortic dissection happened only in 2 (0.4%) 120  |  www.cardiologyinreview.com

patients (if type A alone, only 1 patient = 0.2%). A further comprehensive search for all aortic dissections at the Mayo Clinic during the same period showed 2 additional dissections in BAVs that were undiagnosed until dissection occurred. Although the relative risk of dissection is still estimated to be high at 8.4 times compared with those with TAV, the absolute risk itself appears to be extremely low (0.1%/year at most). From these findings, it is fair to say that we are doing very well in the management of patients with BAV in a real world practice, effectively preventing dissections before they actually happen, and maintaining a normal life expectancy for patients with BAV, at least until their 60s. Of note, even though published in 2011, the study period is from 1980 to 1999, before the release of 1998 US valve guidelines, which had not yet recommended specific surgical indications on BAV aortopathy. The similar clinical course with normal life expectancy and low dissection incidence rate (also estimated 0.1%/year) was reported from another retrospective study from Toronto published around the same time (Table 2).18 The Mayo Clinic study, however, provided concerns about patients with BAV as well. The first was that a substantial portion of patients ultimately required intervention on the AV. Although most were free of severe valve dysfunction at enrollment, more than half (53 ± 10%) were estimated to require AVR over 25 years. The second concern was that a quarter of patients with BAV (25 ± 8%) required aortic surgery over 25 years, even those starting with a relatively normal size aorta (mean 34 ± 9 mm and only 8% > 45 mm at enrollment). Although not explicitly shown, most of the aortic surgery must have been done concomitantly at the time of aortic valve surgery, suggested by the observation that baseline AS was a predictor (predecessor) of new aneurysm formation, and the baseline valve dysfunction-free subgroup had a very low incidence of aortic surgery (5% at 25 years). The same finding was seen in the Toronto study, and all aortic surgery was done concomitantly at the time of aortic valve surgery. A high lifetime incidence of intervention on the AV and/or aorta, with most being performed concomitantly, may not seem that concerning, given the fact that the patients from these large cohort studies enjoyed similar life expectancies as the general population.16–18 However, we should not overlook that this equivalence in survival applies only to patients who were followed up only until they were 60 years old. Another concern not adequately recognized is that the majority of patients who undergo surgery remain at risk of © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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Cardiology in Review  •  Volume 24, Number 3, May/June 2016

Bicuspid Aortic Valve Keeps Eluding Us

TABLE 2.  Comparison of Landmark Natural History Studies Study N Study period Follow-up length (years) Age (years) Male (%) Baseline prevalence of valve dysfunction, moderate or more Baseline prevalence of aortic aneurysm (definition) Aortic dissection incidence (type A) Aortic surgery incidence AVR incidence Survival

Mayo #116

Mayo #217 (Subgroup of Mayo #1)

Toronto18

Toronto Subgroup

416 1980–1999 15 35 69 No significant AS, unclear for AR

212 1980–1999 16 32 65 0%

642 1994–2001 9 35 68 37%

122 1994–2001 9

8% (>45 mm)

15% (>40 mm)

10% (>40 mm)

N = 2(1)/416 (0.2%) N = 49/416 (11.8%), 25% at 25 years N = 133/416(32%), 53% at 25 years 80% at 25 years

N=0 N = 8/212 (3.8%), 5% at 20 years

N = 5(3)/642 (0.5%) N = 43/642 (7%)

N = 38/212 (18%), 24% at 20 years 90% at 20 years

N = 142/642 (22%) 96% at 10 years

0%

N = 1(1)/122

96% at 10 years

AR indicates aortic regurgitation; AS, aortic stenosis; AVR, aortic valve replacement.

additional surgery later in life due to the early timing of the first intervention on the AV, typically in their 50s. Concomitant AVR and aortic surgery, even if as complex as root replacement, can probably be well tolerated by young and otherwise healthy patients with BAV, especially in centers of expertise, without an incremental operative risk compared with isolated AVR.19 However, even the complex first operation does not mean a cure, and these patients are still exposed to reoperation risk as they age, with additional comorbidities. The more complex the initial operation is, the more challenging the second operation may be, with an incremental operative risk. This is a more realistic concern than the risk of aortic dissection. This concern can be better understood by examining studies focusing on the first postoperative course in patients with BAV.

Patients with BAV Status Post AVR It would have been informative to assess a longer followup of the natural history studies above,16–18 extending further after age 60. However, the Mayo Clinic study instead published another study focusing on the postoperative course of patients with BAV who underwent isolated AVR.20 This study reviewed 1286 consecutive patients with BAV who underwent isolated AVR (aorta not resected) during 1960–1995. The mean age of the patients was 58 years, consistent with their prior study finding that half of the patients with BAV underwent AVR before their 60s. Because the study consisted of older patients with a median follow-up of 12 years, this study gives us information on how certain patients with BAV who had AV intervention did after 60 years old. Contrary to the prior 2011 natural history study, the 15-year survival after AVR was lower than the ageand sex-matched general population, starting to diverge 7–8 years after operation and eventually at 52% versus 62% (P < 0.001) at 15 years. Aortic dissection incidence was again extremely low regardless of the presence of baseline aneurysm (defined as >40 mm), 15-year freedom of 99% for baseline aneurysm negative group and 98% for the positive group. This incidence of dissection does not lead to the simple conclusion that isolated AVR alone is good enough as a surgical intervention for patients with BAV, but clearly challenges the notion of the overaggressive approach to intervene on the aorta at the time of AVR. Although not the main goal of this study, another striking but not surprising finding was shown in the same study. Approximately a third of patients (34%, n = 312) required reoperation for the AV during the median follow-up of 12 years, as opposed to only 1% reoperations (n = 11) for aortopathy. Reoperative AVR was an independent predictor of cardiovascular mortality. In the 2011 natural history © 2015 Wolters Kluwer Health, Inc. All rights reserved.

study with the younger cohort, a high incidence of surgery did not compromise survival, and even restored the otherwise compromised survival rate back to normal level. On the contrary, this Mayo Clinic postoperative study showed a negative impact of second operation on survival. By definition, these patients are status post isolated AVR, but it is conceivable that the operative risk at reoperation would be higher, if the initial operation was more complex involving the ascending aorta and/or especially the root. Reoperation after initial root replacement is indeed a challenge even in centers of expertise, with approximately a 7% mortality.21 Therefore, this Mayo Clinic study demonstrates that a second operation on the AV has a more realistic incidence and risk affecting survival than the rare complication of aortic disease. As a comparison to the Mayo study,20 3 other major studies dealing with patients with BAV status post isolated AVR are reviewed focusing on the surgical indication cutoff, reoperation rate, primary reason for reoperation, and adverse aortic events during follow-up (Table 3).22–24 The study by Borger et al,22 often referenced in contemporary aortic or valve guidelines, was the first to recommend an aortic diameter >45 mm as the threshold for concomitant ascending aortic resection during AVR in patients with BAV. The authors adopted a less stringent strategy (50 mm aortic diameter cutoff) than their final recommendation of this study (45 mm), and found among 201 patients with a mean follow-up of 10 years, there was only 1 dissection (0.5%) and a 17% reoperation for prosthetic AV as a primary reason (as opposed to 3.5% for ascending aortic disease as a primary reason). Ten years later, despite the 45-mm threshold recommendation in the previous study, Borger and Girdauskas showed in another study adopting a 50 mm cutoff for aortic intervention that no dissection occurred during the 10-year follow-up in 153 patients with BAV compared with 1.2% in the TAV group.23 The reoperation rate for the AV was relatively low at 4.6%, probably related to the study’s higher use of mechanical valves. The reoperation for dilated aorta as a primary reason occurred in only 3% (n = 5) of patients with BAV (vs. 5% in TAV). The study from the Cleveland Clinic, whose study period was before the 2006 valve guidelines,6 is the only study which adopted the 45-mm threshold for concomitant aortic surgery.24 This “proactive” approach expectedly succeeded in preventing aortic dissection with an incidence of only 0.2% (n = 3) at 10 years in the isolated AVR group (n = 1449), but those treated proactively (AVR + aortic replacement group, n = 361) had a similar incidence of dissection (n = 2, 0.6%). Unlike other studies, the reoperation rate for the AV is not given in this study. Reoperation for aortic disease as the primary reason was only 0.2% in the isolated AVR group (1.1% in AVR + ascending group). www.cardiologyinreview.com  |  121

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TABLE 3.  Comparison of Studies Focusing on the Incidence of Aortic Events Status Post Isolated Aortic Valve Replacement with Different Cutoff Strategies Study

Borger et al22

Mayo20

Intervention at the Study Enrolment

Isolated AVR

Isolated AVR

Isolated AVR

AVR + Aortic Replacement

201 1979–1993 10

1286 1960–1995 12

1449 1993–2003 9

361 1993–2003 9

153 in AS (21 in AR*) 1995–2001 11.5

172 1995–2001 10.5

56 76 AS, 63%; AR, 22%; Mixed, 15% 78

58 72 AS, 77%; AR, 7%; Mixed, 15% 36

56 76 AS, 60%; AR, 30% 69

54 82 AS, 36%; AR, 38% 69

54 73 AS, 100% in 153 (AR 100% in 21*) 7

64 48 AS 100%

N Study period Follow-up length (years) Age (years) Male (%) Indication for AVR

Cleveland24

Girdauskas et al23 Isolated AVR for BAV Isolated AVR for TAV

Bioprosthetic valve 15 use (%) Proactive approach No No Yes Yes No No applied (near 45 mm cutoff) Native aortic 11% (45–50 mm), 32% 39% (>40 mm), 61% 5% (>45 mm), N/A 39% (45–50 mm), 61% 40% (45–50 mm), 60% diameter left after (40–45 mm), 57% (40 mm) (definition) Root phenotype prevalence 20% (28%) (prevalence in those with aortopathy) Root phenotype Age, 51; male, 79%; characteristics RL-BAV, 68%; AR, 32%; AS, 53%

14% (16%) Age 43

69%

74%

14% (19%)

26% (30%)

50%

30% (30%)

Age, 39; male, 100%; RL- Age, 49; male, 90%; RL- Age, N/A; male, N/A; BAV, 100%; AR, 39%; BAV, 92%; AR, 47%; AS, RL-BAV, 11%; AR, 0%; AS, 6% 12% AS, 0%

AR indicates aortic regurgitation; AS, aortic stenosis; BAV, bicuspid aortic valve; CT, computed tomography; Echo, echocardiogram; MRI, magnetic resonance imaging; N/A, not applicable; RL-BAV, right left cusp fusion type bicuspid aortic valve.

confounding effect of hemodynamic and genetic parameters, both should be evaluated within a study rather than separately in different studies, so we can determine the independent predictive value of 1 parameter versus the other. With these parameters jointly evaluated and their significance established, an integrative risk-stratification consisting of both hemodynamic and genetic predictors will likely be possible, leading to a true individualized approach to the management of BAV aortopathy. With these new parameters in mind, one example of surgical classification of BAV based on the aortopathy phenotype and valve function and an individualized approach is proposed in Figure 4 and Table 6.

FORMIDABLE CHALLENGES IN INTERPRETING BAV AORTOPATHY LITERATURE There are unique features in BAV aortopathy, which make implementation and interpretation of its research studies challenging. Here, we start with the principle of aortic size, which should be the basis of all BAV aortopathy studies and yet has not garnered enough attention. Then, the practical problems in statistical analyses of BAV studies will be discussed.

“Normal” Aortic Diameter Is Altered by Age and Location Because the aortic diameter defines major study outcomes of interest in BAV aortopathy, such as dilatation and phenotype, we need to know the reference point of aortic size in the general population (TAV). Hannuksela et al47 showed in a study of the general population (n = 77), cited in the 2010 US aortic guidelines,5 that the aortic size is associated with age independent of body mass index and sex, and the growth rate is different by aortic location with 0.12 mm/ year growth rate in the aortic root and 0.20 mm/year in the ascending aorta (mean 0.16 mm/year). This finding was validated by other larger studies with surprisingly consistent results (Table 7).43,47–50 These findings give us a fundamental principle about aortic size evaluation; “normal” aortic size keeps changing through life, and the growth rate is almost twice as much comparing the aortic root and the ascending aorta. According to a proposed formula among these studies, in subjects in their 50s, a typical age range when the first intervention 126  |  www.cardiologyinreview.com

Valve Function Aortic Phenotype

Normal

AS

AR

Normal

Root

Ascending

FIGURE 4.  Surgical classification of bicuspid aortic valve based on the aortopathy phenotype and valve function. AR indicates aortic regurgitation; AS, aortic stenosis. on the aortic valve in patients with BAV happens, the expected mean, upper normal limit (defined with 2 standard deviations), and aneurysm threshold (a 50% increase from normal diameter) of the ascending aorta, were 33, 40, and 50 mm, respectively. Therefore, 40 mm, sometimes used as a surgical trigger by advocates for aggressive ascending aortic replacement, still falls within the normal range. Moreover, 45 mm, a guideline-based surgical trigger for concomitant aortic replacement, does not even reach the guideline suggested definition of “aneurysm” in this age group. The observed difference in normal growth rate between different parts of the aorta (root vs. ascending) should also be fully appreciated. In the literature, aortic diameter has often been measured either at the root or the ascending aorta or whichever is larger, which was acknowledged as “ambiguous” in the latest guidelines.2 However, with this almost 2-fold difference in growth rate, it is probably reasonable to address them separately. Doing so is critically important because the 2 anatomical components implicate different surgical strategies, with different associated morbidities © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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Cardiology in Review  •  Volume 24, Number 3, May/June 2016

Bicuspid Aortic Valve Keeps Eluding Us

TABLE 6.  Classification of the Individualized Approach to BAV and Its Associated Aortopathy Valve Function

Aortopathy Phenotype

Prophylactic Approach*

Recommended Treatment Options and Comments

1. Normal

A. Normal

−

B. Root type

+

C. Ascending type

−

A. Normal

−

B. Root type

+

C. Ascending type

−

A. Normal

+

B. Root type

++

C. Ascending type

+

No surgical intervention: “normal” aorta may be already exposed to abnormal WSS. If so, closer surveillance‡ needed Valve sparing root replacement +ascending Ao replacement: root type suggests more genetic involvement, and remaining BAV may cause abnormal WSS on ascending portion, so concomitant ascending Ao replacement probably reasonable Ascending Ao replacement only: Ascending type suggests less genetic involvement. WSS is mainly on ascending portion, so better to avoid root replacement AVR only: If aorta is normal even until valve is dysfunctional, genetic is less or least involved. AVR only should be enough. No need to concern WSS after AVR Bentall† + ascending Ao replacement: Root type may suggest genetic involvement, so concomitant ascending Ao replacement probably reasonable AVR + ascending Ao replacement: Most common type. Less genetic involvement suggested. No need for root replacement AV repair or AVR: AV repair will keep aorta at risk of abnormal WSS so follow-up surveillance needed. AR also may be one of the early manifestations of root phenotype so even after AVR, Ao needs to be followed (Valve sparing root replacement or Bentall) + ascending Ao replacement: Genetic involvement most suspected. Concomitant ascending Ao replacement recommended especially if valve is spared because the ascending portion remains at the risk of abnormal WSS (AV repair or AVR or valve sparing root or Bentall) + ascending Ao replacement: root resection may be reasonable especially if BAV spared due to the remaining concern of abnormal WSS and genetic involvement suggested by AR. The combination of AV repair and ascending Ao replacement needs closest follow-up.

2. AS

3. AR

* “−” indicates not recommended; “+,” reasonable; “++,” recommended. † Composite valve-graft conduit replacement of the aortic root. ‡ Standard surveillance interval defined as at least annual based on the latest guidelines. Ao indicates aorta; AR, aortic regurgitation; AS, aortic stenosis; AV, aortic valve; AVR, aortic valve replacement; BAV, bicuspid aortic valve; WSS, wall shear stress.

and potential complications (root replacement vs. ascending aortic replacement vs. both).

The Principle of Aortic Size Measurement Should Always Be Kept in Mind for BAV Studies With the reference point about aortic growth rate given now, we will show how this principle is useful by examining what is the aortic growth rate in BAV subjects compared with TAV in different settings (normal BAV, dysfunctional BAV, and status post AVR). Several studies evaluated aortic growth rate in BAV, not necessarily separately measuring root and ascending portion (Table 8).16,18,42,43,51–55 These studies examined patients from different phases of the BAV natural history, reflected in different prevalence of baseline valve dysfunction. As a starting point, aortic growth rate in “normally functioning” BAV, as reported by Etz et al51 and Michelena et al,16 showed a 2–4 times faster growth rate in the ascending aorta than normal subjects (equal to or about 0.20 mm). As discussed previously, this faster growth rate observed even in the “normal” BAV may be the result of a genetically impaired aortic wall in patients with BAV (genetic) or altered blood flow, resulting increased wall stress that can be generated by normal functioning BAV (hemodynamic) or the combination of both effects. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

How is the aortic growth affected if BAV becomes dysfunctional? Despite discrepancies noted among studies (Table 8),18,42,43,52,53 generally the more valve dysfunction at baseline, the faster the aortic growth rate, suggesting the growth rate is accelerated by progression of BAV dysfunction. Two other trends implied by these studies are as follows: almost twice the difference in growth rate between root and ascending aorta observed in the normal population is maintained in the setting of either normal or dysfunctional BAV; even dysfunctional BAV still shows a relatively slow growth rate, especially in the root portion (0.2–0.5 mm/year) and also in the ascending aorta (0.3–0.9 mm/year). It appears rare that either the aortic root or ascending aorta in the BAV population would reach the definition of “rapid progression” set by guidelines as a surgical threshold for aortic replacement, either by US (5 mm/year)2 or the less aggressive European (2 mm/year)3 consensus. What is the expected aortic growth rate after BAV is removed? According to the principle, the mere fact that the BAV aorta keeps dilating is still a normal finding. Yasuda et al54 investigated the aortic growth rate in BAV after AVR, among patients having AR as a dominant dysfunction (62%). After AVR, patients with BAV showed a progression of 0.03 and 0.18 mm/m2/year in root and ascending portions, equivalent to 0.06 and 0.36 mm/year, respectively (assuming body surface area = 2 m2). Thus, the aortic root growth rate was not www.cardiologyinreview.com  |  127

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Cardiology in Review  •  Volume 24, Number 3, May/June 2016

TABLE 7.  Aortic Growth Rate in the Setting of Tricuspid Aortic Valve Growth Rate (mm/year) N Hannuksela et al47 Devereux et al50 Hager et al48 Wolak et al49 Detaint et al43

Aortic Root (Sinus of Valsalva)

Ascending Aorta (Tubular Portion)

Prevalence of Baseline Valve Dysfunction (%)

0.12 0.10 0.12 N/A 0.09

0.20 N/A 0.15 0.16 0.20

0 0 0 0 0

77 1207 70 4039 51

N/A indicates not applicable.

TABLE 8.  Aortic Growth Rate in the Setting of Bicuspid Aortic Valve Growth Rate (mm/year)

Before aortic valve replacement  Etz et al51  Michelena et al16  Tzemos et al18  Detaint et al43  Della Corte et al42  Ferencik and Pape52†  Davies et al55† After aortic valve replacement  Yasuda et al54  Charitos et al46 Guideline definition of rapid progression

N

Aortic Root (Sinus of Valsalva)

Ascending Aorta (Tubular Portion)

Prevalence of Baseline Valve Dysfunction (%)

158 143* N/A 353 133 68 70

N/A N/A 0.20 0.21 0.30 0.50 N/A

0.77 0.39 0.30 0.42 0.60 0.90 1.90

0 0 37 49 50 60 100

13 361

0.06 0.13

0.36 0.25

0 0

5.0 (US) or 2.0 (Europe)

*Not directly given in the text. Calculated with given aortic measurement in patients having these data available (39.4–35.5 mm divided by the follow-up of 10 years). †Studies showing the aortic growth rate in the BAV in the latest 2014 US valve guidelines. N/A indicates not applicable.

faster than normal (0.1 mm/year), and the ascending portion growth rate appeared just slightly faster than normal (0.2 mm/year). Interestingly, the growth rate was stratified by the baseline valve dysfunction (AS vs. AR) and the relatively faster progression rate observed in the ascending portion was found to be mostly driven by the AR group, which could be explained by the potentially more aggressive factors in the root phenotype as previously discussed, although the limited sample size of 13 BAV subjects is probably not large enough to make a definitive conclusion. In the AS group, the estimated progression rate is only 0.2 mm/year, which is again not faster than the normal growth rate (0.2 mm/year). Recently, Charitos et al46 reported on 361 patients’ status post Ross procedure for BAV and investigated the subsequent aortic growth rate. Of note, the technique used in all patients was subcoronary implantation, preserving the native aortic wall in both the root and ascending portion. The study showed a growth rate of 0.13 mm/year in the root and 0.25 mm/year in the ascending portion, not faster than the one calculated from the age, gender, and body surface area-matched general population of their cohort (and not faster than the normal rate observed in studies in Table 6). Unlike the study by Yasuda et al,54 baseline valve dysfunction did not have any impact on the aortic growth rate. In the latest 2014 US valve guidelines,2 the studies by Ferencik and Pape52 and Davies et al55 are the only studies introduced to show the aortic growth rate in patients with BAV. However, the prevalence of valve dysfunction is high (60% and 100%) in both studies, and high aortic growth rates observed in these studies are the ones in the setting of “BAV aortic growth rate with valve dysfunction” and not generalizable to other settings (no valve dysfunction or after 128  |  www.cardiologyinreview.com

AVR). This subtle difference in aortic growth rate in the setting of AV dysfunction can be difficult to interpret until the aortic measurement principle is fully appreciated. Judging by studies showing the aortic growth rate in patients with BAV in different settings, patients with BAV do have a higher aortic growth rate than TAV patients, but it is still slow, especially in the root and without valve dysfunction. After AVR, the aortic growth rate appears slower and almost equal to TAV subjects,46 but the AR type (or root phenotype) still needs to be investigated for a potentially higher growth rate because of conflicting study results.

Technical Difficulty in Statistical Analyses in BAV Studies On top of difficulties using aortic size as a study outcome, there are technical limitations to overcome when performing statistical analyses for BAV aortopathy studies. First of all, there are too many BAV-related variables. With two more potential variables discussed (hemodynamic parameter and aortopathy phenotype variables), how many variables do we have to control for, when performing risk stratification analysis to predict aortic dilatation? Besides basic patient demographics, such as age and sex, at least the following 5 variables should be included: 1. cusp morphology (RL type, RN type, or LN type), 2. valve dysfunction (normal, stenosis, or regurgitation), 3. hemodynamic parameter (flow pattern, wall shear stress, etc.), 4. aortopathy phenotype (normal, ascending phenotype, and root phenotype), and 5. others (family history, genetics, biomarkers, etc.). © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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Cardiology in Review  •  Volume 24, Number 3, May/June 2016

When the prognostic impact of one subtype from a certain variable is being studied, the ideal situation would be that all patients have information available on all the variables listed above, and also that the sample size is large enough to provide an adequate number for each subtype of all variables. For example, if we want to know the true independent predictive value of RL cusp fusion type on aortic dilatation, we need sufficient information on all other variables and control for them. In the many studies discussed above, patients are often presented with some variables missing or not fully appreciated, making the results of analysis somewhat inconclusive. The high correlation among some variables and resulting multicolinearity is another problem. For example, as previously discussed, AR and root phenotype are known to be highly correlated, and the effect actually attributed to AR may be mistakenly attributed to the root phenotype or vice versa.

Time-Variable Variables The time-variable nature of each variable is the biggest challenge. Among the variables listed above, cusp fusion type (RL, RN, or LN) is the only variable that does not change over time. Other variables do not necessarily stay constant from initial study enrollment and most likely change during the course of the study. For example, valve function is relatively easy to understand, but even this variable may not be progressing in just one direction. The valve dysfunction variable can change from AR at study enrollment to AS during followup, as suggested in several studies. New variables that are still not completely established, such as hemodynamic parameters and aortopathy phenotype, may change more frequently and in a complex fashion. The hemodynamic parameters are probably the most timedependent variables during the course of any BAV study, affected by other variables that also change over time. This time-dependent feature of BAV-related variables, influencing each other over time, makes interpretation or even implementation of longitudinal analysis very challenging. “Baseline” variables depend highly on when BAV subjects are enrolled into the study, during a highly variable clinical and morphologic course. We need to keep in mind that most studies show only one facet of one fact about BAV. Only a multicenter international study, currently ongoing (International Bicuspid Aortic Valve Consortium: NCT01980797) with a target sample of 10,000 and an estimated study completion date of 2033, is expected to give us clear answers.

CONCLUSIONS Despite the high incidence of AV dysfunction requiring intervention, patients with BAV are well managed, enjoying nearly normal longevity up until their 60s. However, there appears to be room for improvement in long-term management. Recent evidence showed that the risk of aortic dissection is real but extremely low, and the further size-dependent intention to prevent aortic dissection may contribute little to the overall management of patients with BAV. For most patients with BAV, the second operation on the diseased AV, repaired or replaced initially, is a much more probable event than adverse aortic events. An overaggressive approach to all patients with BAV, especially for the aortic root, may subject a substantial number of patients with BAV to the unnecessary risk of a more complex initial operation, which may require a reoperation with a higher operative risk. Therefore, simple labeling of “BAV” is clearly outdated, and the key to further survival improvement in patients with BAV appears to lie in a more individualized approach, consisting of adequate vigilance and appropriate timing and selection of the initial operation based on the level of risk each patient has. Several emerging new parameters from both hemodynamic and genetic theories are proposed to more accurately risk stratify the widely heterogeneous entity of patients with BAV and associated aortopathy. The unique challenges associated with BAV studies should always be kept in mind in © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Bicuspid Aortic Valve Keeps Eluding Us

its implementation and interpretation, so that the understanding and appropriate management of BAV aortopathy does not keep eluding us. Our proposed recommendations for the management and surveillance of BAV are summarized in Table 6. REFERENCES 1. Verma S, Yanagawa B, Kalra S, et al. Knowledge, attitudes, and practice patterns in surgical management of bicuspid aortopathy: a survey of 100 cardiac surgeons. J Thorac Cardiovasc Surg. 2013;146:1033–1040.e4. 2. Nishimura RA, Otto CM, Bonow RO, et al; ACC/AHA Task Force Members. 2014 AHA/ACC Guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:e521–e643. 3. Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. 2012;33:2451–2496 4. Svensson LG, Adams DH, Bonow RO, et al. Aortic valve and ascending aorta guidelines for management and quality measures. Ann Thorac Surg. 2013;95(6 suppl):S1–66. 5. Hiratzka LF, Bakris GL, Beckman JA, et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; American Association for Thoracic Surgery; American College of Radiology; American Stroke Association; Society of Cardiovascular Anesthesiologists; Society for Cardiovascular Angiography and Interventions; Society of Interventional Radiology; Society of Thoracic Surgeons; Society for Vascular Medicine. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation. 2010;121:e266–e369. 6. Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 guidelines for the management of patients with valvular heart disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: Endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation. 2006;114:e84–231 7. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2014 update: a report from the American Heart Association. Circulation. 2014;129:e28–e292. 8. Robledo-Carmona J, Rodríguez-Bailón I, Carrasco-Chinchilla F, et al. Hereditary patterns of bicuspid aortic valve in a hundred families. Int J Cardiol. 2013;168:3443–3449. 9. Cripe L, Andelfinger G, Martin LJ, et al. Bicuspid aortic valve is heritable. J Am Coll Cardiol. 2004;44:138–143. 10. Huntington K, Hunter AG, Chan KL. A prospective study to assess the frequency of familial clustering of congenital bicuspid aortic valve. J Am Coll Cardiol. 1997;30:1809–1812. 11. Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation. 2005;111:920–925. 12. Fernandes SM, Khairy P, Sanders SP, et al. Bicuspid aortic valve morphology and interventions in the young. J Am Coll Cardiol. 2007;49:2211–2214. 1 3. Fernandes SM, Sanders SP, Khairy P, et al. Morphology of bicus pid aortic valve in children and adolescents. J Am Coll Cardiol. 2004;44:1648–1651. 14. Sabet HY, Edwards WD, Tazelaar HD, et al. Congenitally bicuspid aortic valves: a surgical pathology study of 542 cases (1991 through 1996) and a literature review of 2,715 additional cases. Mayo Clin Proc. 1999;74:14–26. 15. Beroukhim RS, Kruzick TL, Taylor AL, et al. Progression of aortic dilation in children with a functionally normal bicuspid aortic valve. Am J Cardiol. 2006;98:828–830. 16. Michelena HI, Khanna AD, Mahoney D, et al. Incidence of aortic complications in patients with bicuspid aortic valves. JAMA. 2011;306:1104–1112. 17. Michelena HI, Desjardins VA, Avierinos JF, et al. Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community. Circulation. 2008;117:2776–2784.

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18. Tzemos N, Therrien J, Yip J, et al. Outcomes in adults with bicuspid aortic valves. JAMA. 2008;300:1317–1325. 19. Etz CD, Homann TM, Silovitz D, et al. Long-term survival after the Bentall procedure in 206 patients with bicuspid aortic valve. Ann Thorac Surg. 2007;84:1186–1193; discussion 1193–1184. 20. McKellar SH, Michelena HI, Li Z, et al. Long-term risk of aortic events following aortic valve replacement in patients with bicuspid aortic valves. Am J Cardiol. 2010;106:1626–1633. 21. Etz CD, Plestis KA, Homann TM, et al. Reoperative aortic root and transverse arch procedures: a comparison with contemporaneous primary operations. J Thorac Cardiovasc Surg. 2008;136:860–867, 867.e1. 22. Borger MA, Preston M, Ivanov J, et al. Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve disease? J Thorac Cardiovasc Surg. 2004;128:677–683. 23. Girdauskas E, Disha K, Borger MA, et al. Long-term prognosis of ascending aortic aneurysm after aortic valve replacement for bicuspid versus tricuspid aortic valve stenosis. J Thorac Cardiovasc Surg. 2014;147:276–282. 24. Svensson LG, Kim KH, Blackstone EH, et al. Bicuspid aortic valve surgery with proactive ascending aorta repair. J Thorac Cardiovasc Surg. 2011;142:622–629, 629.e621–623. 25. Eleid MF, Forde I, Edwards WD, et al. Type A aortic dissection in patients with bicuspid aortic valves: clinical and pathological comparison with tricuspid aortic valves. Heart. 2013;99:1668–1674. 26. Svensson LG, Kim KH, Lytle BW, et al. Relationship of aortic cross-sectional area to height ratio and the risk of aortic dissection in patients with bicuspid aortic valves. J Thorac Cardiovasc Surg. 2003;126:892–893. 27. Wang Y, Wu B, Dong L, et al. Type A aortic dissection in patients with bicuspid or tricuspid aortic valves: a retrospective comparative study in 288 Chinese patients. Eur J Cardiothorac Surg. 2013;44:172–177. 28. Rylski B, Blanke P, Beyersdorf F, et al. How does the ascending aorta geometry change when it dissects? J Am Coll Cardiol. 2014;63:1311–1319. 29. Hagan PG, Nienaber CA, Isselbacher EM, et al. The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease. JAMA. 2000;283:897–903. 30. Hope MD, Hope TA, Meadows AK, et al. Bicuspid aortic valve: four-dimensional MR evaluation of ascending aortic systolic flow patterns. Radiology. 2010;255:53–61. 31. Hope MD, Hope TA, Crook SE, et al. 4D flow CMR in assessment of valve-related ascending aortic disease. JACC Cardiovasc Imaging. 2011;4:781–787. 32. Barker AJ, Markl M, Bürk J, et al. Bicuspid aortic valve is associated with altered wall shear stress in the ascending aorta. Circ Cardiovasc Imaging. 2012;5:457–466. 33. Bissell MM, Hess AT, Biasiolli L, et al. Aortic dilation in bicuspid aortic valve disease: flow pattern is a major contributor and differs with valve fusion type. Circ Cardiovasc Imaging. 2013;6:499–507. 34. Mahadevia R, Barker AJ, Schnell S, et al. Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy. Circulation. 2014;129:673–682. 35. Nataatmadja M, West M, West J, et al. Abnormal extracellular matrix protein transport associated with increased apoptosis of vascular smooth muscle cells in Marfan syndrome and bicuspid aortic valve thoracic aortic aneurysm. Circulation. 2003;108(Suppl 1):II329–II334 36. Cotrufo M, Della Corte A, De Santo LS, et al. Different patterns of extracellular matrix protein expression in the convexity and the concavity of the dilated aorta with bicuspid aortic valve: preliminary results. J Thorac Cardiovasc Surg. 2005;130:504–511.

37. Biner S, Rafique AM, Ray I, et al. Aortopathy is prevalent in relatives of bicuspid aortic valve patients. J Am Coll Cardiol. 2009;53:2288–2295. 38. Fazel SS, Mallidi HR, Lee RS, et al. The aortopathy of bicuspid aortic valve disease has distinctive patterns and usually involves the transverse aortic arch. J Thorac Cardiovasc Surg. 2008;135:901–907, 907.e1. 39. Schaefer BM, Lewin MB, Stout KK, et al. The bicuspid aortic valve: an integrated phenotypic classification of leaflet morphology and aortic root shape. Heart. 2008;94:1634–1638. 40. Kang JW, Song HG, Yang DH, et al. Association between bicuspid aortic valve phenotype and patterns of valvular dysfunction and bicuspid aortopathy: comprehensive evaluation using MDCT and echocardiography. JACC Cardiovasc Imaging. 2013;6:150–161. 41. Della Corte A, Bancone C, Quarto C, et al. Predictors of ascending aortic dilatation with bicuspid aortic valve: a wide spectrum of disease expression. Eur J Cardiothorac Surg. 2007;31:397–404; discussion 404. 42. Della Corte A, Bancone C, Buonocore M, et al. Pattern of ascending aortic dimensions predicts the growth rate of the aorta in patients with bicuspid aortic valve. JACC Cardiovasc Imaging. 2013;6:1301–1310. 43. Detaint D, Michelena HI, Nkomo VT, et al. Aortic dilatation patterns and rates in adults with bicuspid aortic valves: a comparative study with Marfan syndrome and degenerative aortopathy. Heart. 2014;100:126–134. 44. Girdauskas E, Disha K, Raisin HH, et al. Risk of late aortic events after an isolated aortic valve replacement for bicuspid aortic valve stenosis with concomitant ascending aortic dilation. Eur J Cardiothorac Surg. 2012;42:832–837; discussion 837. 45. Roberts WC, Vowels TJ, Ko JM, et al. Comparison of the structure of the aortic valve and ascending aorta in adults having aortic valve replacement for aortic stenosis versus for pure aortic regurgitation and resection of the ascending aorta for aneurysm. Circulation. 2011;123:896–903. 46. Charitos EI, Stierle U, Petersen M, et al. The fate of the bicuspid valve aortopathy after aortic valve replacement. Eur J Cardiothorac Surg. 2014;45:e128–e135. 47. Hannuksela M, Lundqvist S, Carlberg B. Thoracic aorta–dilated or not? Scand Cardiovasc J. 2006;40:175–178. 48. Hager A, Kaemmerer H, Rapp-Bernhardt U, et al. Diameters of the thoracic aorta throughout life as measured with helical computed tomography. J Thorac Cardiovasc Surg. 2002;123:1060–1066. 49. Wolak A, Gransar H, Thomson LE, et al. Aortic size assessment by noncontrast cardiac computed tomography: normal limits by age, gender, and body surface area. JACC Cardiovasc Imaging. 2008;1:200–209. 50. Devereux RB, de Simone G, Arnett DK, et al. Normal limits in relation to age, body size and gender of two-dimensional echocardiographic aortic root dimensions in persons ≥15 years of age. Am J Cardiol. 2012;110:1189–1194. 51. Etz CD, Zoli S, Brenner R, et al. When to operate on the bicuspid valve patient with a modestly dilated ascending aorta. Ann Thorac Surg. 2010;90:1884– 1890; discussion 1891. 52. Ferencik M, Pape LA. Changes in size of ascending aorta and aortic valve function with time in patients with congenitally bicuspid aortic valves. Am J Cardiol. 2003;92:43–46. 53. Beck-da-Silva L, de Bold A, Davies R, et al. Effect of bisoprolol on right ventricular function and brain natriuretic peptide in patients with heart failure. Congest Heart Fail. 2004;10:127–132. 54. Yasuda H, Nakatani S, Stugaard M, et al. Failure to prevent progressive dilation of ascending aorta by aortic valve replacement in patients with bicuspid aortic valve: Comparison with tricuspid aortic valve. Circulation. 2003;108 Suppl 1:II291–294 55. Davies RR, Kaple RK, Mandapati D, et al. Natural history of ascending aortic aneurysms in the setting of an unreplaced bicuspid aortic valve. Ann Thorac Surg. 2007;83:1338–1344.

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