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CURRENTOPINION Cardiovascular disease in Williams syndrome

R. Thomas Collins IIa,b

Purpose of review

Williams syndrome is a multisystem disorder seen with some regularity at most pediatric centers and usually fairly often at larger centers. Cardiovascular abnormalities, because of elastin deficiency, are the leading cause of morbidity and mortality in patients with Williams syndrome. The present article presents a review of the most recent developments regarding the cardiovascular issues in Williams syndrome.

Recent findings

Cardiovascular abnormalities occur in 80% of patients with Williams syndrome, the majority of which are arterial stenoses. The stenoses seen in Williams syndrome now appear to arise from deficient circumferential arterial growth. Pharmacological therapies aimed at improving the vascular stenoses have shown some promise in animal models. Surgical outcomes for supravalvar aortic stenosis are good at most centers. Transcatheter interventions are largely ineffective in Williams syndrome. Multilevel surgical pulmonary artery reconstruction has excellent results for peripheral pulmonary artery stenosis. Periprocedural risk stratification and management algorithms may decrease the risk of cardiovascular complications.

Summary

Cardiovascular abnormalities are a major determining factor in the clinical picture and trajectory of patients with Williams syndrome. Advances in surgical techniques, medical therapeutic options, and periprocedural management hold promise for significant improvements in the cardiovascular outcomes of these patients.

Keywords

anesthesia, cardiovascular, medical, surgery, Williams syndrome

INTRODUCTION

Williams syndrome (Online Mendelian Inheritance in Man #194050), or Williams–Beuren syndrome, is a multisystem, congenital disorder affecting approx- imately one in 10 000 live births [1]. Williams syn- drome occurs as the result of a deletion of approximately 1.5 –1.8 Mb on chromosome 7q11.23 [2]. The deletion includes 26 –28 genes and is almost always de novo; however, familial cases have been reported [3]. The ELN gene, which enc- odes the protein elastin, is located near the middle of the commonly deleted region [4]. Deletion of one of the ELN alleles, resulting in hemizygosity of ELN, is responsible for the vascular abnormalities seen in Williams syndrome [5].

THE ROLE OF ELASTIN IN CARDIOVASCULAR ABNORMALITIES

Elastin comprises approximately 50% of the dry weight of the aorta, and is found throughout the arterial tree [6]. Elastin provides distensibility and recoil, allowing for the storage of energy in the

arterial wall during systolic distension and the release of the stored energy during diastolic recoil. This feature of elastin improves the efficiency of the cardiovascular system via the Windkessel effect, a physical phenomenon by which noncontinuous, pulsatile energy can be stored and subsequently released as a continuous stream. In the aorta, the pulsatile flow from the heart is stored in the dis- tended wall during systole. Subsequently, as the aortic wall recoils during diastole, it continues to push the blood further into the distal arterial tree. Thus, via the Windkessel effect, the pulsatile flow from the heart is transformed to continuous flow at the distal arterial bed and capillary level [7]. In

aThe Department of Pediatrics, Division of Cardiology, Stanford Univer- sity School of Medicine and bThe Department of Pediatrics, Division of Cardiology, Lucile Packard Children’s Hospital Stanford, Palo Alto, California, USA

Correspondence to R. Thomas Collins II, MD, Stanford University School of Medicine, 750 Welch Road, Suite 321, Palo Alto, CA 94304, USA. Tel: +1 650 736 7419; e-mail: [email protected]

Curr Opin Pediatr 2018, 30:609–615

DOI:10.1097/MOP.0000000000000664

REVIEW

mailto:[email protected]

addition, the Windkessel effect decreases the after- load on the heart and is vital for coronary artery perfusion during diastole, thereby impairing ven- tricular function [8].

Prior studies have reported that elastin haploin- sufficiency results in subendothelial migration and vascular smooth muscle cell hyperplasia causing encroachment on the vascular lumen and arterial stenoses [9,10]. However, recent work by Jiao et al. [11

] has shown that deficient circumferential growth, and not vascular smooth muscle cell prolif- eration, is the primary determinant of aortic luminal narrowing in the setting of elastin haploinsuffi- ciency and moderate vascular disease. This repre- sents a significant shift in the understanding of the pathophysiology of arterial stenoses in Williams syndrome, one that could shift the approach to future medical therapies [12].

CARDIOVASCULAR ABNORMALITIES IN WILLIAMS SYNDROME

Structural cardiovascular abnormalities, the major- ity of which are stenotic lesions, are the leading cause of morbidity and mortality in patients with Williams syndrome [3]. Cardiovascular defects occur in approximately 80% of patients with Wil- liams syndrome [13], a number that increases to 93% in those who present in the 1st year of life [14]. Supravalvar aortic stenosis (SVAS) occurs in approximately 55% of patients with Williams syn- drome who present in the 1st year of life [14] and 45% of those who present thereafter [13]. The natu- ral history of SVAS lesion severity is mostly one of stability [15]. Branch or peripheral pulmonary artery stenosis (PAS) occurs in approximately 60% of patients presenting in the 1st year of life [14] and �40% of those who present thereafter [15]. The

natural history of PAS is one of progressive improve- ment. A number of other structural cardiac abnor- malities are common in Williams syndrome, with rarer lesions like Ebstein anomaly of the tricuspid valve also having been reported (Table 1).

Other nonstructural cardiovascular issues are common in patients with Williams syndrome. Of those, hypertension is the most common, occurring in 40–50% [36]. Renal artery stenosis, which can be a significant contributor to hypertension, has been reported to occur in 7 –58% of patients with Wil- liams syndrome [13,37 –39,40

]. However, a signif- icant number of patients do not have an identifiable cause for hypertension [41]. Notably, the risk of hypertension is decreased in patients whose dele- tion includes NCF1 [42]. Another less common, but highly concerning, issue for patients with Williams syndrome is a significantly increased risk of sudden

KEY POINTS

� Cardiovascular abnormalities, which occur in the large majority of patients with Williams syndrome, are the leading cause of morbidity and mortality.

� Transcatheter interventions for arterial stenoses in Williams syndrome are rarely of any benefit and may be detrimental.

� In the right hands, multilevel, surgical pulmonary artery reconstruction can have exceptional results in patients with Williams syndrome.

� The risk of cardiovascular events in the periprocedural period can likely be mitigated against in patients with Williams syndrome using a risk stratification plan and periprocedural management algorithm.

Table 1. Structural cardiovascular abnormalities in patients with Williams syndrome

Structural abnormality Frequency

Supravalvar aortic stenosis 35–65% [13,16,17]

Peripheral pulmonary artery stenosis 37–61% [13,17,18]

Long-segment stenosis of the thoracic aortaa 6–14% [17,19]

Ventricular septal defect 8–21% [13,17]

Supravalvar pulmonary stenosis 12% [12]

Abnormal mitral valve 20% [13]

Mitral valve prolapse 15% [20,21]

Mitral valve regurgitation 14% [21]

Abnormal aortic valve 18% [13]

Aortic insufficiency 10% [13]

Abnormal aortic valve cusps 7% [13]

Bicuspid aortic valve 5–12% [13,20]

Valvar aortic stenosis 4% [13]

Coronary artery anomalies 11–27% [13,22]

Ostial stenosis 5–9% [12,13]

Dilated coronary arteriesb 19–23% [22,23]

ALCAPA Rare [12]

Atrial septal defect 3–6% [13,17]

Ebstein anomaly Rare [24–26]

Tetralogy of Fallot Rare [17,27,28]

Total anomalous pulmonary venous return Rare [29–31]

Complete atrioventricular canal defect Rare [32]

Double-chambered right ventricle Rare [33]

Aortopulmonary window Rare [15]

Interrupted aortic arch Rare [34]

Pulmonary artery sling Rare [35]

aLong-segment stenosis of the thoracic aorta is often incorrectly referred to as coarctation of the aorta. bIn cases of severe supravalvar aortic stenosis; ALCAPA, anomalous left coronary artery arising from the pulmonary artery.

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death. Sudden death is 25–100 times more common in patients with Williams syndrome than the gen- eral population [43,44], with the cause being incom- pletely understood. The majority of events have been in the periprocedural setting [45

], and are often associated with the concomitant presence of bilateral outflow tract obstruction and coronary artery stenosis [43], though this is not always the case [43,46]. Prolongation of the corrected QT (QTc) interval on ECG is present in 13% of patients with Williams syndrome [46], which may be a contribut- ing factor in the increased risk of sudden death [47]. Notably, an increased risk of sudden death has not been reported in nonsyndromic elastin arteriopa- thy, a condition caused by mutations in ELN and characterized by a cardiovascular phenotype nearly identical to Williams syndrome. QTc prolongation is not associated with nonsydromic elastin arterio- pathy [48], suggesting that the QTc prolongation in Williams syndrome could play a role in the increased risk of sudden death.

MANAGEMENT OF CARDIOVASCULAR ISSUES IN PATIENTS WITH WILLIAMS SYNDROME

Medical management

Medical therapies to address cardiovascular issues in Williams syndrome are largely directed toward the treatment of hypertension. When considering hypertension and subsequent management thereof, it is imperative to determine if renal artery stenosis is present. Angiotensin converting enzyme inhibitors (ACEI), which are often first-line therapy for hyper- tension in the general population, are generally, relatively contraindicated in the setting of renal artery stenosis, as they pose a risk of renal dysfunc- tion [49]. Conversely, calcium channel blockers of the dihydropiridine class are often the first line of therapy for hypertension in Williams syndrome, as they are effective and do not carry a risk in the setting of renal artery stenosis [15]. b-blockers are another option for hypertension management, and they may have additional benefits regarding poten- tial arrhythmia risk and sudden death [15].

Recently, Owens et al. [50 &&

] have reported important findings from their study of renal hemo- dynamics and blood pressure (BP) in an elastin heterozygous (ELNþ/�) murine model. Although BP in the ELNþ/� mice was similar to wild-type controls, renal vascular resistance was increased and renal blood flow was lower. Further, there was damage to the glomerular filtration barrier at the level of the podocyte foot processes, a finding independent of BP, indicating elastin deficiency

produces structural defects in the kidney. Further, the renal interlobar artery basal tone and myogenic response were noted to be elevated in ELNþ/�, a finding that was normalized by the administration of candesartan, an AT1 blocker (ARB). These find- ings suggest that ARBs could be an attractive anti- hypertensive therapy for patients with Williams syndrome, though cautious use would be required in the setting of renal artery stenosis, as ARBs can have similar effects to ACEI.

Pharmacological therapies to treat arterial stenosis

Effective medical therapies aimed at improving the vascular abnormalities in patients with Williams syn- drome have so far been elusive. However, multiple recent studies in murine models of elastin haploin- sufficiency have shown promising results that may 1 day translate into effective therapies for patients.

Minoxidil, a KATP channel opener and vasodilator used for hypertension therapy, has been known for 20 years to increase arterial elastin content [51]. Slove et al. [52] subsequently reported similar findings of increased aortic elastin concentration in elastin defi- cient rats treated with minoxidil; however, they reported better results from diazoxide, a different KATP channel opener. In 2017, Coquand-Gandit et al. [53

] reported minoxidil increases tropoelastin and induced elastin expression in aged, adult mice. More recently, Knutsen et al. [54

] reported their results of minoxidil administration in the ELN�/�

murine model. They found that minoxidil decreased arterial stiffness, improved arterial diameter, and restored blood flow to the carotid and cerebral arter- ies. The findings persisted for weeks following dis- continuation of the medication. Although these results suggest that oral therapy with minoxidil has the potential to improve the arterial abnormalities in Williams syndrome, they must be considered with caution. The measures used by Knutsen et al. to assess arterial stiffness are BP-dependent. Since the BPs were lower in treated ELN�/� mice, decreased arterial stiff- ness would be expected to also be found, as was the case. It is unclear from the described methodology if the authors controlled for BP in their analysis. Another factor to consider in this study is the arterial wall thickness was actually increased in the treated mice. Because the stain used in the presented histo- logical slides specifically stains for elastin, other com- ponents of the arterial wall that contribute to wall thickness cannot be delineated. In addition, promis- ing results in animal models do not always translate into highly successful therapies in humans [55,56]. Further investigation of the arterial effects of minox- idil in patients with Williams syndrome will need to be conducted. Nevertheless, the results of these

Cardiovascular disease in Williams syndrome Collins

studies are highly encouraging with regard to future potential use in patients with Williams syndrome. Further, given its proven benefit in the treatment of hypertension in the general population, the incorpo- ration of minoxidil into the antihypertensive arma- mentarium for patients with Williams syndrome seems reasonable in appropriate clinical contexts.

Rapamycin, which blocks cellular proliferation via inhibition of the mammalian target of rapamycin complex, has also shown promising results in labo- ratory and mouse models. Kinnear et al. [57] first reported the use of rapamycin in smooth muscle cell cultures derived from induced pluripotent stem cells from patients with Williams syndrome. In that study, rapamycin decreased the pathologic smooth muscle cell proliferation rate. In 2013, Li et al. [58] reported that rapamycin reduced smooth muscle cell prolifer- ation and aortic obstruction in ELN�/� mouse pups and prevented medial hyperlamellation in heterozy- gotes. Notably, the improvement in the vascular findings did not result in increased lifespan of the mice. This finding has not, thus far, been reproduced in humans. More recently, Jiao et al. [59

] have shown that rapamycin and its analogs prevent aortic fibrosis and stiffening. Although these studies using rapamy- cin in cell cultures and mice are encouraging, no studies with rapamycin have been done in patients with Williams syndrome. Further, rapamycin ther- apy comes with significant side effects that will need to be considered.

Laboratory testing for other potential therapies has shown some promise, but the data are limited. The inhibition of microRNA-29 in cell cultures has been shown to increase elastin in the extracellular matrix [60]. Similarly, the inhibition of extracellular signal-regulated kinases 1/2 phosphorylation increases elastin synthesis [61]. Misra et al. [62] have recently reported that celengitide, an integrin b3 and b5 inhibitor, decreases arterial muscularization, and stenosis.

Taken together, there are multiple pharmacolog- ical therapies that show promise in laboratory models of elastin haploinsufficiency. Although data from studies of these therapies in patients with Williams syndrome are currently unavailable, the results from the laboratory studies hold significant hope that beneficial pharmacological therapies will be eluci- dated that will improve the vascular phenotype in patients with Williams syndrome, hopefully to such a degree as to avoid the need for surgical intervention.

Surgical management

Interventions for the various cardiovascular abnor- malities seen in Williams syndrome, whether cath- eter-based or surgical, are performed in one-third of

patients, with 75% of those undergoing their first intervention by 5 years of age [13]. The risk for major adverse cardiovascular events (in-hospital death, cardiac arrest, or postoperative mechanical circula- tory support) in patients with Williams syndrome who undergo heart surgery is significantly increased in those who undergo surgery for bilateral outflow tract obstruction; complex left ventricular (LV) out- flow tract obstruction; and procedures involving coronary artery repair [63].

Surgery is most often performed for SVAS, and in the large majority of cases, surgery for SVAS is undertaken by 15 years of age [13,17,64]. In a large, single-center cohort of all patients with SVAS (41% with Williams syndrome), survival for SVAS surgery was 90�7% at 5 years and 82�10% at 20 years [65]. In that cohort, need for subsequent SVAS surgery was low. Recently, Roemers et al. [66] reported a single-center experience of 49 patients (24/49, 49% with diagnosed Williams syndrome) who under- went SVAS repair and had follow-up of up to 52 years. Those authors found no difference in out- comes for symmetrical (Brom’s three-patch tech- nique or slide aortoplasty) versus asymmetrical (single patch or inverted Y-shaped patch) techni- ques. Need for reoperation for SVAS was reported in 16% of cases, the majority of which (6/8, 75%) had a prior history of discrete SVAS. In the setting of the diffuse-type of SVAS, wherein the whole aorta is stenotic, some authors have reported that as many as 35% will require reintervention [67].

Interventions for PAS have largely been trans- catheter in nature [13]. This approach in a cohort of patients with Williams syndrome was first reported by Geggel et al. [68]. On the contrary, the literature reporting transcatheter dilation of the pulmonary arteries is not particularly convincing of its benefit in Williams syndrome. In Geggel’s original report, the mean right ventricular (RV) pressure did not change as a result of the balloon dilation. Further, the difference between the RV and systemic BPs, referred to as the RV-to-aorta ratio (RV : Ao), only decreased greater than 20% in four of the 39 proce- dures. Subsequently, Cunningham reported on transcatheter outcomes in 69 patients (23 with Wil- liams syndrome) who underwent transcatheter dila- tion for PAS [69]. In the patients with Williams syndrome, the RV : Ao did not change. Further, the need for reintervention was very high; 75% at 5 years for transcatheter and 23% at 5 years for surgical. In addition, transcatheter stent implanta- tion in patients with Williams syndrome can often induce a marked neointimal hyperplasia response resulting in worse arterial stenosis [70,71]. As such, stent implantation in patients with Williams syn- drome should largely be avoided.

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Although outcomes for surgical intervention of PAS in patients with Williams syndrome have been suboptimal at most institutions, multilevel surgical pulmonary artery reconstruction, as reported by Mainwaring et al. [72], has been shown to carry a high degree of success. Mid-term results of patients who have undergone this surgical approach (includ- ing 19 patients with Williams syndrome) indicate a decrease of RV : Ao from 0.88�0.07 preoperatively to 0.40�0.04 postoperatively, with a maintenance of the outcome over 4�3 years of follow-up [73&&]. When contrasted against the results of transcatheter interventions, multilevel surgical pulmonary artery reconstruction should be the first-line management strategy in patients with Williams syndrome.

Orthotopic heart transplantation is an option for many children and young adults with congenital heart disease. Only recently have González-López et al. [74

] reported the first case of heart transplant in a patient with Williams syndrome. Because of a range of considerations regarding the success of heart transplantation, such as likely marked after- load on both the RV (due to PAS) and the LV (due to diffuse aortic stenosis), most patients with Williams syndrome would not be viable candidates.

Periprocedural and anesthesia management

As previously noted, sudden death is markedly increased in patients with Williams syndrome, most

often in the periprocedural period. Olsen et al. [75] published their experience of 108 anesthestic events in 29 patients over a 35-year period. Twelve anesthetic administrations (11%) were associated with a cardiac complication, two of which included cardiac arrest (1.9%), including one patient who died (0.9% mortal- ity). In 2016, Latham et al. [76] reported their experi- ence of 141 anesthestic events in 48 patients (42 with Williams syndrome) over a 23-year period. In that study, 16 anesthetic administrations (11%) were asso- ciated with intraprocedural complications, seven of which were cardiac arrests (5% of anesthetics). In total, 25% of patients experienced intraprocedural compli- cations. Bilateral outflow tract obstruction was com- mon in those who had complications.

The risk of complications reported by both Olsen et al. and Latham et al. far exceed that seen by this author in hundreds of patients with Williams syn- drome at three different institutions. The reasons for these differences may include a number of things such as era of the studies; change in management over time; lack of a Williams syndrome-specific approach to periprocedural management at the study institutions; differences in experience level with Wil- liams syndrome; and recall bias. Nevertheless, because of the increased risk, whatever the level, increasing attention and periprocedural planning are being given to patients with Williams syndrome. As a result, two recent articles have been published

Table 2. Risk stratification and prehydration plan prior to anesthetic administration in patients with Williams syndrome

Low risk (standard anesthetic care)

Moderate risk (morning IV placement and hydration �2 h prior to anesthetic)

High riska (admit preceding evening with IV fluid administration overnightb)

Age >20 years Hypertension Age <3 years

No cardiac involvement greater than mild supravalvar or branch PAS

Moderate supravalvar or branch PAS History of adverse cardiovascular event

Normal ECG Mild bilateral outflow tract obstruction Preprocedural arrhythmia

No renal artery involvement Renal artery stenosis Bilateral outflow tract obstruction of �moderate severity

Renal dysfunction SVAS gradient of �40 mmHg and the presence of left ventricular hypertrophy

QTc on ECG >450 ms, but <500 ms Coronary artery involvement

Airway abnormalities, lung disease, or severe gastroesophageal reflux

Diffuse stenosis of the thoracic aorta

Right ventricular pressure �75% systemic �Moderate left or right ventricular hypertrophy Symptoms or ECG signs of ischemia

QTc on ECG�500 ms

IV, intravenous catheter; ms, milliseconds; PAS, pulmonary artery stenosis; PICC, peripherally inserted central venous catheter; QTc, corrected QT interval on ECG; SVAS, supravalvar aortic stenosis. Adapted with permission [45

]. aIf patient has prior history of obstructive lesions that have been surgically repaired, then he/she should NOT be considered to be high risk. Rather, determination of risk should be based on current anatomic issues. bReliable IV placement is imperative. Strong consideration should be given to having placement performed by the vascular access team. In addition, for certain patients with particularly high-risk lesions (significant coronary arterial stenosis and outflow tract obstruction), placement of a PICC line should be considered, especially if the patient is to go on to have a surgical procedure.

Cardiovascular disease in Williams syndrome Collins

outlining periprocedural risk stratification and man- agement plans aimed at mitigating the risk of cardio- vascular complications [45

,77]. Table 2 outlines the risk stratification system and preprocedural hydra- tion plan used by this author.

CONCLUSION

Cardiovascular abnormalities are present in the large majority of patients with Williams syndrome, and the need for interventions is common. Advance- ments in surgical techniques provide options for significant improvements in the cardiovascular dis- ease burden for these patients. Recent cell culture and animal model work suggest that successful pharma- cological therapies aimed at ameliorating the vascu- lar abnormalities in Williams syndrome will soon be realized, thus decreasing the need for surgery. Peri- procedural cardiovascular complications are much more common in patients with Williams syndrome than the general populations. If used appropriately, recently published periprocedural risk stratification and management guidelines may decrease peripro- cedural complications significantly.

Acknowledgements

None.

Financial support and sponsorship

The current work was supported, indirectly, by the Divi- sion of Cardiology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California, USA.

Conflicts of interest

There are no conflicts of interest.

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Cardiovascular disease in Williams syndrome Collins