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Prevalence and Impact of Coexistent Bicuspid Aortic Valve in Hypertrophic Cardiomyopathy
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ORIGINAL ARTICLE
Heart, Lung and Circulation (2017) xx, 1–8 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2017.01.020
Prevalence and Impact of Coexistent Bicuspid Aortic Valve in Hypertrophic Cardiomyopathy Ratnasari Padang, PhD, MBBS, Bernard J. Gersh, MBChB, DPhil, Steve R. Ommen, MD, Jeffrey B. Geske, MD * Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA Received 16 November 2016; accepted 26 January 2017; online published-ahead-of-print xxx
Background
The association between bicuspid aortic valve (BAV) and hypertrophic cardiomyopathy (HCM) has been reported but its true prevalence is unknown. This study investigated the prevalence and clinical impact of coexistent BAV in a large referral HCM population.
Methods
Retrospective analysis of 3765 echocardiograms between 2004 and 2014 in 2640 consecutive patients with HCM was performed to assess for BAV. Patients with coexistent conditions were studied.
Results
Twenty-three patients (0.9%) were identified with coexisting BAV and HCM. Mean age was 52 16 years, 18 males (78%), 16 with NYHA functional class I/II at initial evaluation (70%). A family history of HCM was present in five patients (22%); none had a family history of BAV or aortopathy. Maximal left ventricular wall thickness was 24 6 mm; the majority had either reverse curve or sigmoid septal morphology. Moderate or greater aortic valve dysfunction was present in seven patients (30%), BAV-related aortopathy in 18 patients (78%) and dynamic left ventricular outflow tract (LVOT) obstruction in nine patients (39%). Three patients had combined LVOT obstruction and aortic stenosis. Median time from diagnosis of BAV or HCM to last follow-up was 11 12.5 years. At last follow-up, 22% had undergone BAV-related surgeries, 30% had septal reduction therapy (SRT), and 17% had combined SRT and BAV-related surgeries. Overall survival was 95% at 10 years.
Conclusions
This study reported a 0.9% prevalence of BAV among HCM population, similar to the general population. Aortopathy and LVOT obstruction were common, necessitating cardiac interventions in over one-third of cases. Long-term survival appeared favourable.
Keywords
Bicuspid aortic valve Hypertrophic cardiomyopathy Prevalence Outcome
Introduction Bicuspid aortic valve (BAV) is the most common congenital heart disease, with a prevalence of approximately 1% in the general population [1,2]. Over a 25-year period after BAV diagnosis, the risk for aortic valve replacement (AVR) is greater than 50%, for aneurysm formation (50 mm) is [6_TD$IF] 26%, and for aortic surgery is 25% [1]. Bicuspid aortic valve
is a highly heritable trait, indicating an underlying genetic basis [3,4], however, apart from infrequent mutations in NOTCH1 and GATA5 genes [3], the underlying genetic basis of BAV remains largely unknown. Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy, occurring in 0.2% of the general population [5]. Hypertrophic cardiomyopathy is a genetically and phenotypically heterogeneous disorder,
*Corresponding author at: Department of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester MN 55905 USA. Tel.:+1 507 284 1648; Fax:+1 507 266 0228., Email: [email protected] © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Padang R, et al. Prevalence and Impact of Coexistent Bicuspid Aortic Valve in Hypertrophic Cardiomyopathy. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.01.020
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characterised by prominent myocardial hypertrophy in the absence of other loading conditions. Hypertrophic cardiomyopathy is inherited in an autosomal dominant fashion with variable expressivity and age-related penetrance, due to mutations in 11 or more genes encoding the cardiac sarcomeric proteins [6]. Clinical manifestations of HCM are usually the result of left ventricular outflow tract (LVOT) obstruction, which occurs in up to 70% of those affected [7], systolic and/or diastolic heart failure, arrhythmias, and sudden cardiac death (SCD). The association between BAV and HCM has been reported in the literature as early as the 1960s [8–10]. However, the prevalence of BAV amongst contemporary HCM populations is unknown, but it is hypothesised to be similar to that of the general population. The implication of coexistent BAV and HCM on clinical outcome is also unclear. This study sought to determine the prevalence of coexisting BAV amongst a large referral HCM population, describe the clinical characteristics[7_TD$IF], and discuss the management of this unique patient cohort.
Material and Methods Study Population The Mayo Clinic Institutional Review Board approved the study and granted a waiver of informed consent given the retrospective nature of this chart review study. An echocardiographic database search for all patients seen at the Mayo Clinic, Rochester, Minnesota, USA between January 1st 2004 to December 31st 2014 with the diagnosis of HCM was performed. A separate search for BAV, identified on transthoracic (TTE) or transoesophageal echocardiography (TEE) during the same study period, was undertaken. All echocardiographic studies in patients with coexistent BAV and HCM were manually reviewed for confirmation. Baseline demographics, family history[8_TD$IF], and clinical course were reviewed from the electronic medical record.
Diagnostic Criteria for BAV and HCM Diagnoses were confirmed via chart review. Hypertrophic cardiomyopathy was diagnosed clinically, based on the presence of unexplained myocardial hypertrophy (wall thickness 15 mm) in a nondilated left ventricle, in the absence of local or systemic aetiologies capable of producing the magnitude of hypertrophy evident [6,11]. Hypertrophic cardiomyopathy phenocopies (eg. amyloidosis, Fabry’s disease) were excluded. Mild systemic hypertension was not an exclusion criterion in the diagnosis of HCM. The diagnosis of BAV was based on anatomic evaluation of the aortic valve on short axis view at TTE or TEE by demonstration of two aortic valve cusps in systole, with only two commissures framing an elliptical systolic orifice [12]. In patients who underwent aortic valve surgery, BAV was confirmed on pathology specimen.
Echocardiography All patients underwent comprehensive two dimensional (2D) and Doppler echocardiography with commercially available ultrasound equipment performed in accordance with American Society of Echocardiography guidelines [12–14]. Assessment of septal morphology was performed using the apical long-axis view at end diastole, as previously described [15,16], and classified as sigmoid, reverse curve, apical or neutral. Measurement of the resting LVOT gradient was performed by continuous-wave Doppler interrogation of the LVOT from an apical window and calculated using the modified Bernoulli equation. Resting LVOT obstruction was defined as a peak instantaneous outflow gradient 30 mmHg under [9_TD$IF]resting conditions. In patients with resting LVOT gradient <30 mmHg, provocative manoeuvers including Valsalva and amyl nitrite administration were used per laboratory protocol. Provocable obstruction was defined as development of an LVOT gradient 30 mmHg with provocation. Grading [10_TD$IF]of aortic valve stenosis [1_TD$IF]and regurgitation severity was made according to published guidelines [12,17]. Aortic root and ascending aorta measurements were made on the parasternal long axis views using the leading edge-to-leading edge convention at end-diastole. Aortopathy was defined as a sinus of Valsalva or ascending aorta dimension 40 mm [18]. Moderate ascending aortic dilatation was defined as maximal aortic dimension of 45 mm and aneurysmal dilatation 50 mm.
Statistical Analysis [12_TD$IF]Continuous variables were presented as mean standard deviation (SD[13_TD$IF]). Categorical variables were expressed as number (percentage[14_TD$IF]). For outcome assessment, time zero represented the time of initial diagnosis of either BAV or HCM. Subsequent events, including tachyarrhythmias, septal reduction therapies (SRT), BAV-related surgeries, and death were determined by medical record review. For all-cause mortality and cumulative survival free of SRT, BAV-related surgery[15_TD$IF], or death, medical records of patients with unknown outcome were censored at the time of last clinical follow-up. All-cause mortality was estimated using the Kaplan-Meier method. Expected survival was estimated using age- and sex-matched published death rates from the United States general population. The actual and expected survival rates were compared using a one sample log-rank test [19]. All statistical analyses were performed with the use of JMP version 10.0 software (SAS Institute Inc., Cary, NC, USA), and p value <0.05 was considered statistically significant.
Results Study Population and Prevalence of Coexistent BAV and HCM Between January 1st, 2004 and December 31st, 2014, 3765 echocardiographic studies in 2640 consecutive patients with
Please cite this article in press as: Padang R, et al. Prevalence and Impact of Coexistent Bicuspid Aortic Valve in Hypertrophic Cardiomyopathy. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.01.020
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Clinical characteristics of the study population are listed in Table 1. Eighteen patients (78%) were male, mean age 52 16 years (range 17–80) at index evaluation. Mean age of first diagnosis of either BAV or HCM was 45 17 years. Most patients (70%) were New York Heart Association (NYHA) functional class I or II. A family history of HCM was present in five patients (22%); none had a family history of BAV or aortopathy. Hypertrophic cardiomyopathy genetic testing was performed in six patients (26%), three of [16_TD$IF]whom were positive for pathogenic MYBPC3 or MYH7 gene mutations. Of note, one male patient (age 67 at last follow-up) also had coarctation of the aorta (diagnosed at age 5), with end-toend anastomosis repair at age 10. This patient had HCM (diagnosed at age 60) with reverse curve septal morphology, maximal wall thickness of 34 mm, right-left BAV fusion morphology with mild stenosis and regurgitation, and a mildly dilated ascending aorta.
fusion was found in 19 patients (83%). At least moderate aortic valve dysfunction was present in seven patients (30%); three with at least moderate aortic stenosis, three with at least moderate aortic regurgitation[19_TD$IF], and one with mixed moderate aortic stenosis and regurgitation. In those with at least moderate aortic stenosis, two patients had apical HCM and one patient had reverse curve septal morphology, maximal wall thickness 29 mm, and moderate aortic stenosis. In the one patient with moderate mixed aortic valve disease, the septal morphology was sigmoid curve (maximal wall thickness 24 mm) and HCM was diagnosed 20 years earlier when the aortic valve was sclerotic with mild regurgitation but without any stenosis. Bicuspid aortic valve-related aortopathy was present in 18 patients (78%); moderate ascending aortic dilatation in nine (39%) including two (9%) with aneurysmal dilatation. The mean sinus of Valsalva and ascending aortic dimensions were 40 4 mm and 42 5 mm, respectively. Dynamic obstruction was present in 11 patients (48%; Table 3), most commonly affecting the LVOT, with resting obstruction (gradient 30 mmHg) in five patients. Three patients with LVOT obstruction (33%) had coexistent aortic stenosis; all three underwent myectomy. Intra-operative TEE confirmed the severity of aortic stenosis in each case (with one case of mild, moderate and severe aortic stenosis found). In a patient with the severe aortic stenosis, the diagnosis was suspected clinically and confirmed surgically on direct inspection of the aortic valve; a combined myectomy and AVR was performed.
Echocardiographic Features
Clinical Outcomes
Detailed echocardiographic characterisation of the study cohort [17_TD$IF]is listed in Table 2 and illustrated in Figure 2. The maximal wall thickness was 24 6 mm and [18_TD$IF]the majority had either reverse curve (n = 9, 39%) or sigmoid septal morphology (n = 7; 31%). Bicuspid aortic valve with right-left cusp
The median time from the initial diagnosis of BAV and/or HCM to the last follow-up was 11 12.5 years (range, 1–62 years). The overall survival from the time of either HCM and/or BAV diagnosis was 95%, 95% and 71% at 5-, 10- and 20-year follow-up, respectively, which was no different than
HCM and 13,440 echocardiographic studies in 5430 consecutive patients with BAV were performed. Manual inspection of studies with overlapping criteria identified 23 unrelated patients with coexistent BAV and HCM. This yielded a prevalence of 0.9% of coexistent BAV among patients with HCM and a 0.4% prevalence of coexistent HCM in patients with BAV identified by echocardiography at our institution (Figure 1). Assuming BAV occurs in 1% of the general population [1,2], it can be extrapolated that the prevalence of coexistent BAV and HCM to be less than 1 in 10,000.
Clinical Characteristics
Figure 1 Prevalence of coexisting BAV and HCM detected during echocardiography studies between 2004 and 2014.
Please cite this article in press as: Padang R, et al. Prevalence and Impact of Coexistent Bicuspid Aortic Valve in Hypertrophic Cardiomyopathy. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.01.020
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Table 1 Baseline characteristics at index evaluation at Mayo Clinic (n = 23). Age, years
Table 2 Echocardiographic parameters of patients with coexistent BAV and HCM (n = 23).
52 16
HCM subtype
(range, 17–80)
Reverse curve
9 (39)
Male
18 (78)
Sigmoid curve
7 (31)
Age at diagnosis of either
45 17
Neutral
3 (13)
HCM or BAV, years
Apical
4 (17)
BMI, kg/m2
32 4
Maximal wall thickness, mm
24 6
SBP, mmHg Heart rate, beats per minute
127 13 65 11
Left ventricular end diastolic dimension, mm Left ventricular ejection fraction, %
48 7 66 7
NYHA functional class III-IV
7 (30)
Greater than mild mitral regurgitation
7 (31)
Presyncope or syncope
6 (26)
E/A ratio
1.2 0.8
Hypertension
15 (65)
Medial E/e` ratio
17 10
Coronary artery disease
4 (17)
Left atrial volume index, ml/m2[2_TD$IF]
42 13
Atrial fibrillation
1 (4)
Estimated PASP, mmHg
37 26
Ventricular tachyarrhythmias
8 (35)
SAM
16 (70)
3 (13) 5 (22)
Nonobstructive physiology (<30 mmHg) Obstructive physiology (30 mmHg)
12 (52) 11 (48)
5 (22)
Presence of apical pouch
1 (4)
3 (13)
BAV morphology
VT/VF NSVT on Holter Internal cardioverter-defibrillator Primary prevention
2 (9)
Fused right-left coronary cusps
19 (83)
Family history of HCM
5 (22)
Fused right-non coronary cusps
2 (9)
Family history of SCD
3 (13)
Fused left-non coronary cusps
1 (4)
Family history of BAV or aortopathy
0 (0)
True bicuspid
1 (4)
Coexisting coarctation of the aorta Medications
1 (4)
Secondary prevention
Aortic valve function At least moderate regurgitation
3 (13)
Beta-receptor antagonist
14 (61)
At least moderate stenosis
3 (13)
ACE inhibitor or ARB
10 (43)
Moderate stenosis and regurgitation
1 (4)
Calcium-channel blocker
6 (26)
Aortopathyy
18 (78)
Diuretic
10 (43)
Sinus of Valsalva diameter, mm
40 4
BNP, pg/mL (n = 10)
233 370
Ascending aortic diameter, mm
42 5
NT-pro BNP, pg/mL (n = 12) Peak VO2, predicted maximal aerobic capacity (n = 15)
[3_TD$IF]839 1273 75% 21% predicted
Values are mean SD or n (%). PASP, pulmonary artery systolic pressure;
Positive HCM genetic
3 (50)
outflow tract; RVOT, right ventricular outflow tract.
testing (tested n = 6)
SAM, systolic anterior motion of the mitral valve; LVOT, right ventricular y
Aortopathy was considered present when the maximal dimension of the sinus of Valsalva or ascending aorta reaches 40 mm or greater.
Values are mean SD or n (%). HCM, hypertrophic cardiomyopathy; BAV, bicuspid aortic valve; BSA, body surface area; BMI, body mass index; SBP, systolic blood pressure; NYHA, New York Heart Association; SCD, sudden cardiac death; VT, ventricular tachycardia; VF, ventricular fibrillation; NSVT, non-sustained VT; ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; BNP, brain natriuretic peptide, measured using fluorescence immunoassay (Biosite Diagnostics, San Diego, CA, USA); NT-proBNP, N-terminal prohormone of BNP, measured using electrochemiluminescence immunoassay (Roche Diagnostics, Indianapolis, IN, USA).
all-cause [20_TD$IF]survival of an age- and sex-matched United States Caucasian population (p = 0.75 by log-rank test; Figure 3A). From index diagnosis, the survival free from SRT, BAVrelated surgery or death was 91%, 60% and 40% at 5-, 10and 15-year follow-up, respectively (Figure 3B). At last follow-up (Table 4), three patients (13%) had developed new atrial fibrillation, five (22%) had BAV-related surgeries[21_TD$IF], and seven (30%) had septal reduction therapy (SRT), most
commonly in form of surgical myectomy. This included four patients (17%) with combined SRT and BAV-related surgeries. Four patients (17%) underwent AVR for either aortic stenosis (n = 2) or regurgitation (n = 2). Three deaths (13%) occurred during long-term follow-up; one from metastatic small cell cancer at age 63, two patients died at age 58 and 82, which were 2 and 11 years, respectively, following their surgical myectomy[2_TD$IF], due to unascertained cause.
Discussion This is the first study to evaluate the prevalence of coexistent BAV in a large HCM population, in addition to a description of the clinical characteristics of this unique group of patients. An estimated prevalence of 0.9% for coexistent BAV and HCM was identified. Assuming that BAV occurs in 1% of
Please cite this article in press as: Padang R, et al. Prevalence and Impact of Coexistent Bicuspid Aortic Valve in Hypertrophic Cardiomyopathy. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.01.020
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Figure 2 Illustrative images of a patient with coexisting BAV and HCM. Panel A, Parasternal long-axis view showing HCM with sigmoid septal morphology (asterix; maximum septal wall thickness 20 mm) and asymmetric closure of the aortic valve leaflets (white arrow) suggestive of BAV. Panel B, M-mode echocardiography at the tips of the mitral valve level showing prominent septal hypertrophy and SAM with septal contact. Panel C, Doppler interrogation of the LVOT showing a peak instantaneous resting LVOT gradient of 115 mmHg. Panel D, Colour Doppler assessment across the mitral valve and LVOT demonstrating the presence of severe SAM-associated mitral regurgitation and LVOT obstruction during systole. Panel E, Parasternal short axis view showing BAV with right-left cusps fusion. Panel F, Parasternal long axis of the ascending aorta showing severe ascending aortic dilatation.
the population, the prevalence of coexistent BAV and HCM within the general population would affect <1:10,000 individuals. Complications were common amongst this cohort, with BAV-related aortopathy and LVOT obstruction present in 78% and 39% of patients, respectively. Interventions for BAV and/or HCM-related complications were required in 39% of patients. However, long-term outcomes were favourable, with survival similar to that of healthy age- and sexmatched control population. Previous literature has suggested a possible common genetic aetiology of coexistent BAV and HCM [10]. The 0.9% prevalence of BAV among patients with HCM in this study is similar to the 1% prevalence of BAV in the general population [1,2]. Male predominance is also comparable to that of BAV in the general population (3:1) [4]. These data suggest the relationship is sporadic, as opposed to a genetic association. Although sample size limitations may affect results, the absence of positive family history of BAV or aortopathy among all patients with coexistent conditions further supports this observation. The 0.4% prevalence of coexistent HCM among patients with BAV [23_TD$IF]1is higher than the
estimated prevalence of HCM in the general population of 1 in 500 [5]. This may reflect referral bias. Management of combined BAV and HCM differs from that of isolated HCM. Left ventricular outflow tract obstruction and implantable cardioverter-defibrillator (ICD) implantation occurred less commonly in this cohort (39% and 22%, respectively), although the proportion of patients requiring SRT appeared similar (30%) [20]. Concomitant BAV resulted in additional surgical complexity, with 22% of subjects requiring aortic valve and/or aortic surgery. Outcome of patients with coexistent BAV and HCM was not previously known. With contemporary surveillance and management strategies, life expectancy of adults with isolated BAV or isolated HCM is similar to the general population [20–23]. Whether compounding the haemodynamic insult of diastolic dysfunction, dynamic LVOT obstruction and progressive aortic valve disease would alter survival was unknown. This study would argue against this, showing survival of patients with coexistent conditions to be similar to that with isolated HCM [20] and to an age- and sexmatched control populations.
Please cite this article in press as: Padang R, et al. Prevalence and Impact of Coexistent Bicuspid Aortic Valve in Hypertrophic Cardiomyopathy. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.01.020
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Table 3 Characterisation of those with obstruction (n = 11). Age, years
66 12
NHYA functional class III-IV
5 (45)
Table 4 Clinical outcome of patients with coexistent BAV and HCM. Clinical outcome
5 (45)
Sigmoid curve
5 (45)
Neutral
1 (10)
Rest obstruction Provocable obstruction
Atrial fibrillation
Left ventricular mid-cavity obstruction
2 (18)
RVOT obstruction Peak instantaneous resting LVOT
1 (9)
Myectomy
5 (45)
Septal reduction therapy
7 (30)
66 11 52 18 (24–71)
6 1
Aortic valve replacement
4 (17)
60 9
Aortic surgeryy
4 (17)
60 9
Combined septal reduction surgery and BAV related
4 (17)
64 7
3 (13)
68 13
Death
gradient, mmHg (n = 9) 3 (33)
9 (39)
surgery
55 46
Combined LVOT obstruction and any degree of aortic stenosis*[4_TD$IF]
4 (17)
Any cardiac surgery or intervention
Alcohol septal ablation
Site of flow obstruction 9 (82)
*
Surgical myectomy
5 (45) [5_TD$IF]6 (55)
LVOT obstruction
Age at time of event, years
HCM subtype Reverse curve
n
Values are mean SD (range) or n (%). *
Three of these 4 patients developed new onset atrial fibrillation after their index evaluation at the Mayo Clinic.
y
Three for ascending aortic aneurysm and one for coarctation repair.
Values are mean SD or n (%). *
Refer to text for details.
Although survival is unaffected in combined BAV and HCM, management of these patients entails unique decision-making, and is summarised in Figure 4. Serial echocardiographic screening of the aorta should be a component of imaging surveillance. If cardiac MRI is pursued for risk stratification in HCM, aortic angiography should be considered to exclude BAV-related aortopathy and coarctation. Management of coexisting hypertension should be individualised, with avoidance of dynamic LVOT obstruction exacerbation from excess afterload or preload reduction.
Our preference is to start with a beta-receptor antagonist, consistent with HCM guidelines [11]. Obstructive lesions in series pose an interventional challenge. In patients with a combined maximal instantaneous gradient of >40 mmHg across the LVOT and aortic valve with medically refractory symptoms despite maximal therapy, a surgical approach is recommended. We favour surgical myectomy over alcohol septal ablation given the ability to concurrently address aortic valve dysfunction and aorta pathology. If the patient is not a surgical candidate and alcohol septal ablation is under consideration, haemodynamic catheterisation is of value, as there are distinct
Figure 3 Kaplan-Meier curve for overall survival of patients with coexistent BAV and HCM (solid line) vs an otherwisehealthy age- and gender-matched control (broken line), Figure 3A; and survival free of SRT, BAV-related surgery or death from the time of initial diagnosis of either BAV or HCM in the study population, Figure 3B. SRT, septal reduction therapy.
Please cite this article in press as: Padang R, et al. Prevalence and Impact of Coexistent Bicuspid Aortic Valve in Hypertrophic Cardiomyopathy. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.01.020
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Figure 4 Summary of clinical considerations in the management of patients with coexistent BAV and HCM. See text for details. Central figure demonstrating a patient with coexisting BAV and HCM (dotted blue line = severely increased septal wall thickness (40 mm); white circle around the aortic valve with insert demonstrating the presence of BAV with right-left cusps fusion morphology). AV, atrioventricular; ICD, internal cardioverter defibrillator; SRT, septal reduction therapy; SCD, sudden cardiac death.
limitations to non-invasive quantitation of serial stenoses by Doppler echocardiography. While close inspection of the aortic valve leaflets by TEE can be helpful, invasive haemodynamic catheterisation allows accurate delineation of anatomic location and degree of obstruction at each site [24]. Finally, concomitant BAV and HCM has an impact on family screening. Imaging of first degree relatives should assess for the presence of left ventricular hypertrophy, aortic valve morphology and ascending aortic dimension. Ascending aortic dilatation is highly prevalent (32%) among first degree relatives of patients with BAV, even those with tricuspid aortic valves [25]. A strategy of echocardiographic surveillance is what we have adopted.
Study Limitations The reported prevalence of coexistent BAV and HCM in this study may be overestimated from referral bias. This study utilised an electronic echocardiographic database search, thus patients may have been missed if AVR occurred prior to index evaluation or if the diagnoses of BAV or HCM was missed. The combined use of cardiac CT or MR imaging should be considered in future studies to improve identification of patients with combined pathologies. Although this represents the largest studied population of coexistent BAV and HCM, the cohort was still small, despite a large tertiary referral population. The rate of complications could be overestimated due to referral bias. Larger, pooled cohorts with long-term follow-up would be beneficial to validate these findings. Furthermore, comparative outcome analysis between the study population and cohorts with either isolated HCM or isolated BAV were not feasible given the small size of the study cohort with combined conditions and the
wide spectrum of phenotypic heterogeneity seen among patients with isolated HCM and isolated BAV, which would make meaningful comparison challenging, even after adjusting for age and gender.
Conclusions In this study, the prevalence of BAV among patients with HCM was comparable to that of the general population, consistent with disorders of unrelated genetic origin. Surgically-relevant aortopathy and LVOT obstruction were found commonly amongst these patients, necessitating cardiac interventions in a significant proportion of cases. However, long-term survival of patients with coexistent BAV and HCM appeared favourable and similar to an age- and sex-matched control population. Unique management dilemmas exist in patients with coexistent HCM and BAV.
Authors Contributions RP and JBG contributed to study design, data acquisition, analysis, drafting and revision of the manuscript. BJG and SRO contributed to data analysis, drafting and critical revision of the manuscript. All authors approved the final manuscript.
Funding Source This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Please cite this article in press as: Padang R, et al. Prevalence and Impact of Coexistent Bicuspid Aortic Valve in Hypertrophic Cardiomyopathy. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.01.020
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Disclosures No disclosure. [12]
Conflict of Interest
[13]
None declared.
Acknowledgments The authors would like to thank Mr. David Hodge for his assistance with statistical analysis.
[14]
[15]
[16]
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[25]
Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;58:e212–60. Baumgartner H, Hung J, Bermejo J, Chambers JB, Evangelista A, Griffin BP, et al. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. J Am Soc Echocardiogr 2009; 22:1–23. quiz 101-2. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28:1–39. e14. Quinones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002;15:167–84. Geske JB, Bos JM, Gersh BJ, Ommen SR, Eidem BW, Ackerman MJ. Deformation patterns in genotyped patients with hypertrophic cardiomyopathy. Eur Heart J Cardiovasc Imaging 2014;15:456–65. Binder J, Ommen SR, Gersh BJ, Van Driest SL, Tajik AJ, Nishimura RA, et al. Echocardiography-guided genetic testing in hypertrophic cardiomyopathy: septal morphological features predict the presence of myofilament mutations. Mayo Clin Proc 2006;81:459–67. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin 3rd JP, Guyton RA, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: Executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2438–88. Borger MA, Preston M, Ivanov J, Fedak PW, Davierwala P, Armstrong S, et al. Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve disease? J Thorac Cardiovasc Surg 2004; 128:677–83. Therneau TM, Offord J. Technical Report Number 63, Expected survival based on hazard rates (update). Rochester, Minnesota: Section of Biostatistics, Mayo Clinic; 1999. Maron BJ, Rowin EJ, Casey SA, Link MS, Lesser JR, Chan RH, et al. Hypertrophic Cardiomyopathy in Adulthood Associated With Low Cardiovascular Mortality With Contemporary Management Strategies. J Am Coll Cardiol 2015;65:1915–28. Hebl VB, Miranda WR, Ong KC, Hodge DO, Bos JM, Gentile F, et al. The Natural History of Nonobstructive Hypertrophic Cardiomyopathy. Mayo Clin Proc 2016;91:279–87. Michelena HI, Desjardins VA, Avierinos JF, Russo A, Nkomo VT, Sundt TM, et al. Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community. Circulation 2008;117:2776–84. Tzemos N, Therrien J, Yip J, Thanassoulis G, Tremblay S, Jamorski MT, et al. Outcomes in adults with bicuspid aortic valves. JAMA 2008;300:1317–25. Scantlebury DC, Geske JB, Nishimura RA. Limitations of Doppler echocardiography in the evaluation of serial stenoses. Circ Cardiovasc Imaging 2013;6:850–2. Biner S, Rafique AM, Ray I, Cuk O, Siegel RJ, Tolstrup K. Aortopathy is prevalent in relatives of bicuspid aortic valve patients. J Am Coll Cardiol 2009;53:2288–95.
Please cite this article in press as: Padang R, et al. Prevalence and Impact of Coexistent Bicuspid Aortic Valve in Hypertrophic Cardiomyopathy. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.01.020
ORIGINAL ARTICLE
Heart, Lung and Circulation (2017) xx, 1–8 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2017.01.020
Prevalence and Impact of Coexistent Bicuspid Aortic Valve in Hypertrophic Cardiomyopathy Ratnasari Padang, PhD, MBBS, Bernard J. Gersh, MBChB, DPhil, Steve R. Ommen, MD, Jeffrey B. Geske, MD * Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA Received 16 November 2016; accepted 26 January 2017; online published-ahead-of-print xxx
Background
The association between bicuspid aortic valve (BAV) and hypertrophic cardiomyopathy (HCM) has been reported but its true prevalence is unknown. This study investigated the prevalence and clinical impact of coexistent BAV in a large referral HCM population.
Methods
Retrospective analysis of 3765 echocardiograms between 2004 and 2014 in 2640 consecutive patients with HCM was performed to assess for BAV. Patients with coexistent conditions were studied.
Results
Twenty-three patients (0.9%) were identified with coexisting BAV and HCM. Mean age was 52 16 years, 18 males (78%), 16 with NYHA functional class I/II at initial evaluation (70%). A family history of HCM was present in five patients (22%); none had a family history of BAV or aortopathy. Maximal left ventricular wall thickness was 24 6 mm; the majority had either reverse curve or sigmoid septal morphology. Moderate or greater aortic valve dysfunction was present in seven patients (30%), BAV-related aortopathy in 18 patients (78%) and dynamic left ventricular outflow tract (LVOT) obstruction in nine patients (39%). Three patients had combined LVOT obstruction and aortic stenosis. Median time from diagnosis of BAV or HCM to last follow-up was 11 12.5 years. At last follow-up, 22% had undergone BAV-related surgeries, 30% had septal reduction therapy (SRT), and 17% had combined SRT and BAV-related surgeries. Overall survival was 95% at 10 years.
Conclusions
This study reported a 0.9% prevalence of BAV among HCM population, similar to the general population. Aortopathy and LVOT obstruction were common, necessitating cardiac interventions in over one-third of cases. Long-term survival appeared favourable.
Keywords
Bicuspid aortic valve Hypertrophic cardiomyopathy Prevalence Outcome
Introduction Bicuspid aortic valve (BAV) is the most common congenital heart disease, with a prevalence of approximately 1% in the general population [1,2]. Over a 25-year period after BAV diagnosis, the risk for aortic valve replacement (AVR) is greater than 50%, for aneurysm formation (50 mm) is [6_TD$IF] 26%, and for aortic surgery is 25% [1]. Bicuspid aortic valve
is a highly heritable trait, indicating an underlying genetic basis [3,4], however, apart from infrequent mutations in NOTCH1 and GATA5 genes [3], the underlying genetic basis of BAV remains largely unknown. Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy, occurring in 0.2% of the general population [5]. Hypertrophic cardiomyopathy is a genetically and phenotypically heterogeneous disorder,
*Corresponding author at: Department of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester MN 55905 USA. Tel.:+1 507 284 1648; Fax:+1 507 266 0228., Email: [email protected] © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
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characterised by prominent myocardial hypertrophy in the absence of other loading conditions. Hypertrophic cardiomyopathy is inherited in an autosomal dominant fashion with variable expressivity and age-related penetrance, due to mutations in 11 or more genes encoding the cardiac sarcomeric proteins [6]. Clinical manifestations of HCM are usually the result of left ventricular outflow tract (LVOT) obstruction, which occurs in up to 70% of those affected [7], systolic and/or diastolic heart failure, arrhythmias, and sudden cardiac death (SCD). The association between BAV and HCM has been reported in the literature as early as the 1960s [8–10]. However, the prevalence of BAV amongst contemporary HCM populations is unknown, but it is hypothesised to be similar to that of the general population. The implication of coexistent BAV and HCM on clinical outcome is also unclear. This study sought to determine the prevalence of coexisting BAV amongst a large referral HCM population, describe the clinical characteristics[7_TD$IF], and discuss the management of this unique patient cohort.
Material and Methods Study Population The Mayo Clinic Institutional Review Board approved the study and granted a waiver of informed consent given the retrospective nature of this chart review study. An echocardiographic database search for all patients seen at the Mayo Clinic, Rochester, Minnesota, USA between January 1st 2004 to December 31st 2014 with the diagnosis of HCM was performed. A separate search for BAV, identified on transthoracic (TTE) or transoesophageal echocardiography (TEE) during the same study period, was undertaken. All echocardiographic studies in patients with coexistent BAV and HCM were manually reviewed for confirmation. Baseline demographics, family history[8_TD$IF], and clinical course were reviewed from the electronic medical record.
Diagnostic Criteria for BAV and HCM Diagnoses were confirmed via chart review. Hypertrophic cardiomyopathy was diagnosed clinically, based on the presence of unexplained myocardial hypertrophy (wall thickness 15 mm) in a nondilated left ventricle, in the absence of local or systemic aetiologies capable of producing the magnitude of hypertrophy evident [6,11]. Hypertrophic cardiomyopathy phenocopies (eg. amyloidosis, Fabry’s disease) were excluded. Mild systemic hypertension was not an exclusion criterion in the diagnosis of HCM. The diagnosis of BAV was based on anatomic evaluation of the aortic valve on short axis view at TTE or TEE by demonstration of two aortic valve cusps in systole, with only two commissures framing an elliptical systolic orifice [12]. In patients who underwent aortic valve surgery, BAV was confirmed on pathology specimen.
Echocardiography All patients underwent comprehensive two dimensional (2D) and Doppler echocardiography with commercially available ultrasound equipment performed in accordance with American Society of Echocardiography guidelines [12–14]. Assessment of septal morphology was performed using the apical long-axis view at end diastole, as previously described [15,16], and classified as sigmoid, reverse curve, apical or neutral. Measurement of the resting LVOT gradient was performed by continuous-wave Doppler interrogation of the LVOT from an apical window and calculated using the modified Bernoulli equation. Resting LVOT obstruction was defined as a peak instantaneous outflow gradient 30 mmHg under [9_TD$IF]resting conditions. In patients with resting LVOT gradient <30 mmHg, provocative manoeuvers including Valsalva and amyl nitrite administration were used per laboratory protocol. Provocable obstruction was defined as development of an LVOT gradient 30 mmHg with provocation. Grading [10_TD$IF]of aortic valve stenosis [1_TD$IF]and regurgitation severity was made according to published guidelines [12,17]. Aortic root and ascending aorta measurements were made on the parasternal long axis views using the leading edge-to-leading edge convention at end-diastole. Aortopathy was defined as a sinus of Valsalva or ascending aorta dimension 40 mm [18]. Moderate ascending aortic dilatation was defined as maximal aortic dimension of 45 mm and aneurysmal dilatation 50 mm.
Statistical Analysis [12_TD$IF]Continuous variables were presented as mean standard deviation (SD[13_TD$IF]). Categorical variables were expressed as number (percentage[14_TD$IF]). For outcome assessment, time zero represented the time of initial diagnosis of either BAV or HCM. Subsequent events, including tachyarrhythmias, septal reduction therapies (SRT), BAV-related surgeries, and death were determined by medical record review. For all-cause mortality and cumulative survival free of SRT, BAV-related surgery[15_TD$IF], or death, medical records of patients with unknown outcome were censored at the time of last clinical follow-up. All-cause mortality was estimated using the Kaplan-Meier method. Expected survival was estimated using age- and sex-matched published death rates from the United States general population. The actual and expected survival rates were compared using a one sample log-rank test [19]. All statistical analyses were performed with the use of JMP version 10.0 software (SAS Institute Inc., Cary, NC, USA), and p value <0.05 was considered statistically significant.
Results Study Population and Prevalence of Coexistent BAV and HCM Between January 1st, 2004 and December 31st, 2014, 3765 echocardiographic studies in 2640 consecutive patients with
Please cite this article in press as: Padang R, et al. Prevalence and Impact of Coexistent Bicuspid Aortic Valve in Hypertrophic Cardiomyopathy. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.01.020
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Clinical characteristics of the study population are listed in Table 1. Eighteen patients (78%) were male, mean age 52 16 years (range 17–80) at index evaluation. Mean age of first diagnosis of either BAV or HCM was 45 17 years. Most patients (70%) were New York Heart Association (NYHA) functional class I or II. A family history of HCM was present in five patients (22%); none had a family history of BAV or aortopathy. Hypertrophic cardiomyopathy genetic testing was performed in six patients (26%), three of [16_TD$IF]whom were positive for pathogenic MYBPC3 or MYH7 gene mutations. Of note, one male patient (age 67 at last follow-up) also had coarctation of the aorta (diagnosed at age 5), with end-toend anastomosis repair at age 10. This patient had HCM (diagnosed at age 60) with reverse curve septal morphology, maximal wall thickness of 34 mm, right-left BAV fusion morphology with mild stenosis and regurgitation, and a mildly dilated ascending aorta.
fusion was found in 19 patients (83%). At least moderate aortic valve dysfunction was present in seven patients (30%); three with at least moderate aortic stenosis, three with at least moderate aortic regurgitation[19_TD$IF], and one with mixed moderate aortic stenosis and regurgitation. In those with at least moderate aortic stenosis, two patients had apical HCM and one patient had reverse curve septal morphology, maximal wall thickness 29 mm, and moderate aortic stenosis. In the one patient with moderate mixed aortic valve disease, the septal morphology was sigmoid curve (maximal wall thickness 24 mm) and HCM was diagnosed 20 years earlier when the aortic valve was sclerotic with mild regurgitation but without any stenosis. Bicuspid aortic valve-related aortopathy was present in 18 patients (78%); moderate ascending aortic dilatation in nine (39%) including two (9%) with aneurysmal dilatation. The mean sinus of Valsalva and ascending aortic dimensions were 40 4 mm and 42 5 mm, respectively. Dynamic obstruction was present in 11 patients (48%; Table 3), most commonly affecting the LVOT, with resting obstruction (gradient 30 mmHg) in five patients. Three patients with LVOT obstruction (33%) had coexistent aortic stenosis; all three underwent myectomy. Intra-operative TEE confirmed the severity of aortic stenosis in each case (with one case of mild, moderate and severe aortic stenosis found). In a patient with the severe aortic stenosis, the diagnosis was suspected clinically and confirmed surgically on direct inspection of the aortic valve; a combined myectomy and AVR was performed.
Echocardiographic Features
Clinical Outcomes
Detailed echocardiographic characterisation of the study cohort [17_TD$IF]is listed in Table 2 and illustrated in Figure 2. The maximal wall thickness was 24 6 mm and [18_TD$IF]the majority had either reverse curve (n = 9, 39%) or sigmoid septal morphology (n = 7; 31%). Bicuspid aortic valve with right-left cusp
The median time from the initial diagnosis of BAV and/or HCM to the last follow-up was 11 12.5 years (range, 1–62 years). The overall survival from the time of either HCM and/or BAV diagnosis was 95%, 95% and 71% at 5-, 10- and 20-year follow-up, respectively, which was no different than
HCM and 13,440 echocardiographic studies in 5430 consecutive patients with BAV were performed. Manual inspection of studies with overlapping criteria identified 23 unrelated patients with coexistent BAV and HCM. This yielded a prevalence of 0.9% of coexistent BAV among patients with HCM and a 0.4% prevalence of coexistent HCM in patients with BAV identified by echocardiography at our institution (Figure 1). Assuming BAV occurs in 1% of the general population [1,2], it can be extrapolated that the prevalence of coexistent BAV and HCM to be less than 1 in 10,000.
Clinical Characteristics
Figure 1 Prevalence of coexisting BAV and HCM detected during echocardiography studies between 2004 and 2014.
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Table 1 Baseline characteristics at index evaluation at Mayo Clinic (n = 23). Age, years
Table 2 Echocardiographic parameters of patients with coexistent BAV and HCM (n = 23).
52 16
HCM subtype
(range, 17–80)
Reverse curve
9 (39)
Male
18 (78)
Sigmoid curve
7 (31)
Age at diagnosis of either
45 17
Neutral
3 (13)
HCM or BAV, years
Apical
4 (17)
BMI, kg/m2
32 4
Maximal wall thickness, mm
24 6
SBP, mmHg Heart rate, beats per minute
127 13 65 11
Left ventricular end diastolic dimension, mm Left ventricular ejection fraction, %
48 7 66 7
NYHA functional class III-IV
7 (30)
Greater than mild mitral regurgitation
7 (31)
Presyncope or syncope
6 (26)
E/A ratio
1.2 0.8
Hypertension
15 (65)
Medial E/e` ratio
17 10
Coronary artery disease
4 (17)
Left atrial volume index, ml/m2[2_TD$IF]
42 13
Atrial fibrillation
1 (4)
Estimated PASP, mmHg
37 26
Ventricular tachyarrhythmias
8 (35)
SAM
16 (70)
3 (13) 5 (22)
Nonobstructive physiology (<30 mmHg) Obstructive physiology (30 mmHg)
12 (52) 11 (48)
5 (22)
Presence of apical pouch
1 (4)
3 (13)
BAV morphology
VT/VF NSVT on Holter Internal cardioverter-defibrillator Primary prevention
2 (9)
Fused right-left coronary cusps
19 (83)
Family history of HCM
5 (22)
Fused right-non coronary cusps
2 (9)
Family history of SCD
3 (13)
Fused left-non coronary cusps
1 (4)
Family history of BAV or aortopathy
0 (0)
True bicuspid
1 (4)
Coexisting coarctation of the aorta Medications
1 (4)
Secondary prevention
Aortic valve function At least moderate regurgitation
3 (13)
Beta-receptor antagonist
14 (61)
At least moderate stenosis
3 (13)
ACE inhibitor or ARB
10 (43)
Moderate stenosis and regurgitation
1 (4)
Calcium-channel blocker
6 (26)
Aortopathyy
18 (78)
Diuretic
10 (43)
Sinus of Valsalva diameter, mm
40 4
BNP, pg/mL (n = 10)
233 370
Ascending aortic diameter, mm
42 5
NT-pro BNP, pg/mL (n = 12) Peak VO2, predicted maximal aerobic capacity (n = 15)
[3_TD$IF]839 1273 75% 21% predicted
Values are mean SD or n (%). PASP, pulmonary artery systolic pressure;
Positive HCM genetic
3 (50)
outflow tract; RVOT, right ventricular outflow tract.
testing (tested n = 6)
SAM, systolic anterior motion of the mitral valve; LVOT, right ventricular y
Aortopathy was considered present when the maximal dimension of the sinus of Valsalva or ascending aorta reaches 40 mm or greater.
Values are mean SD or n (%). HCM, hypertrophic cardiomyopathy; BAV, bicuspid aortic valve; BSA, body surface area; BMI, body mass index; SBP, systolic blood pressure; NYHA, New York Heart Association; SCD, sudden cardiac death; VT, ventricular tachycardia; VF, ventricular fibrillation; NSVT, non-sustained VT; ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; BNP, brain natriuretic peptide, measured using fluorescence immunoassay (Biosite Diagnostics, San Diego, CA, USA); NT-proBNP, N-terminal prohormone of BNP, measured using electrochemiluminescence immunoassay (Roche Diagnostics, Indianapolis, IN, USA).
all-cause [20_TD$IF]survival of an age- and sex-matched United States Caucasian population (p = 0.75 by log-rank test; Figure 3A). From index diagnosis, the survival free from SRT, BAVrelated surgery or death was 91%, 60% and 40% at 5-, 10and 15-year follow-up, respectively (Figure 3B). At last follow-up (Table 4), three patients (13%) had developed new atrial fibrillation, five (22%) had BAV-related surgeries[21_TD$IF], and seven (30%) had septal reduction therapy (SRT), most
commonly in form of surgical myectomy. This included four patients (17%) with combined SRT and BAV-related surgeries. Four patients (17%) underwent AVR for either aortic stenosis (n = 2) or regurgitation (n = 2). Three deaths (13%) occurred during long-term follow-up; one from metastatic small cell cancer at age 63, two patients died at age 58 and 82, which were 2 and 11 years, respectively, following their surgical myectomy[2_TD$IF], due to unascertained cause.
Discussion This is the first study to evaluate the prevalence of coexistent BAV in a large HCM population, in addition to a description of the clinical characteristics of this unique group of patients. An estimated prevalence of 0.9% for coexistent BAV and HCM was identified. Assuming that BAV occurs in 1% of
Please cite this article in press as: Padang R, et al. Prevalence and Impact of Coexistent Bicuspid Aortic Valve in Hypertrophic Cardiomyopathy. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.01.020
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Figure 2 Illustrative images of a patient with coexisting BAV and HCM. Panel A, Parasternal long-axis view showing HCM with sigmoid septal morphology (asterix; maximum septal wall thickness 20 mm) and asymmetric closure of the aortic valve leaflets (white arrow) suggestive of BAV. Panel B, M-mode echocardiography at the tips of the mitral valve level showing prominent septal hypertrophy and SAM with septal contact. Panel C, Doppler interrogation of the LVOT showing a peak instantaneous resting LVOT gradient of 115 mmHg. Panel D, Colour Doppler assessment across the mitral valve and LVOT demonstrating the presence of severe SAM-associated mitral regurgitation and LVOT obstruction during systole. Panel E, Parasternal short axis view showing BAV with right-left cusps fusion. Panel F, Parasternal long axis of the ascending aorta showing severe ascending aortic dilatation.
the population, the prevalence of coexistent BAV and HCM within the general population would affect <1:10,000 individuals. Complications were common amongst this cohort, with BAV-related aortopathy and LVOT obstruction present in 78% and 39% of patients, respectively. Interventions for BAV and/or HCM-related complications were required in 39% of patients. However, long-term outcomes were favourable, with survival similar to that of healthy age- and sexmatched control population. Previous literature has suggested a possible common genetic aetiology of coexistent BAV and HCM [10]. The 0.9% prevalence of BAV among patients with HCM in this study is similar to the 1% prevalence of BAV in the general population [1,2]. Male predominance is also comparable to that of BAV in the general population (3:1) [4]. These data suggest the relationship is sporadic, as opposed to a genetic association. Although sample size limitations may affect results, the absence of positive family history of BAV or aortopathy among all patients with coexistent conditions further supports this observation. The 0.4% prevalence of coexistent HCM among patients with BAV [23_TD$IF]1is higher than the
estimated prevalence of HCM in the general population of 1 in 500 [5]. This may reflect referral bias. Management of combined BAV and HCM differs from that of isolated HCM. Left ventricular outflow tract obstruction and implantable cardioverter-defibrillator (ICD) implantation occurred less commonly in this cohort (39% and 22%, respectively), although the proportion of patients requiring SRT appeared similar (30%) [20]. Concomitant BAV resulted in additional surgical complexity, with 22% of subjects requiring aortic valve and/or aortic surgery. Outcome of patients with coexistent BAV and HCM was not previously known. With contemporary surveillance and management strategies, life expectancy of adults with isolated BAV or isolated HCM is similar to the general population [20–23]. Whether compounding the haemodynamic insult of diastolic dysfunction, dynamic LVOT obstruction and progressive aortic valve disease would alter survival was unknown. This study would argue against this, showing survival of patients with coexistent conditions to be similar to that with isolated HCM [20] and to an age- and sexmatched control populations.
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Table 3 Characterisation of those with obstruction (n = 11). Age, years
66 12
NHYA functional class III-IV
5 (45)
Table 4 Clinical outcome of patients with coexistent BAV and HCM. Clinical outcome
5 (45)
Sigmoid curve
5 (45)
Neutral
1 (10)
Rest obstruction Provocable obstruction
Atrial fibrillation
Left ventricular mid-cavity obstruction
2 (18)
RVOT obstruction Peak instantaneous resting LVOT
1 (9)
Myectomy
5 (45)
Septal reduction therapy
7 (30)
66 11 52 18 (24–71)
6 1
Aortic valve replacement
4 (17)
60 9
Aortic surgeryy
4 (17)
60 9
Combined septal reduction surgery and BAV related
4 (17)
64 7
3 (13)
68 13
Death
gradient, mmHg (n = 9) 3 (33)
9 (39)
surgery
55 46
Combined LVOT obstruction and any degree of aortic stenosis*[4_TD$IF]
4 (17)
Any cardiac surgery or intervention
Alcohol septal ablation
Site of flow obstruction 9 (82)
*
Surgical myectomy
5 (45) [5_TD$IF]6 (55)
LVOT obstruction
Age at time of event, years
HCM subtype Reverse curve
n
Values are mean SD (range) or n (%). *
Three of these 4 patients developed new onset atrial fibrillation after their index evaluation at the Mayo Clinic.
y
Three for ascending aortic aneurysm and one for coarctation repair.
Values are mean SD or n (%). *
Refer to text for details.
Although survival is unaffected in combined BAV and HCM, management of these patients entails unique decision-making, and is summarised in Figure 4. Serial echocardiographic screening of the aorta should be a component of imaging surveillance. If cardiac MRI is pursued for risk stratification in HCM, aortic angiography should be considered to exclude BAV-related aortopathy and coarctation. Management of coexisting hypertension should be individualised, with avoidance of dynamic LVOT obstruction exacerbation from excess afterload or preload reduction.
Our preference is to start with a beta-receptor antagonist, consistent with HCM guidelines [11]. Obstructive lesions in series pose an interventional challenge. In patients with a combined maximal instantaneous gradient of >40 mmHg across the LVOT and aortic valve with medically refractory symptoms despite maximal therapy, a surgical approach is recommended. We favour surgical myectomy over alcohol septal ablation given the ability to concurrently address aortic valve dysfunction and aorta pathology. If the patient is not a surgical candidate and alcohol septal ablation is under consideration, haemodynamic catheterisation is of value, as there are distinct
Figure 3 Kaplan-Meier curve for overall survival of patients with coexistent BAV and HCM (solid line) vs an otherwisehealthy age- and gender-matched control (broken line), Figure 3A; and survival free of SRT, BAV-related surgery or death from the time of initial diagnosis of either BAV or HCM in the study population, Figure 3B. SRT, septal reduction therapy.
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Figure 4 Summary of clinical considerations in the management of patients with coexistent BAV and HCM. See text for details. Central figure demonstrating a patient with coexisting BAV and HCM (dotted blue line = severely increased septal wall thickness (40 mm); white circle around the aortic valve with insert demonstrating the presence of BAV with right-left cusps fusion morphology). AV, atrioventricular; ICD, internal cardioverter defibrillator; SRT, septal reduction therapy; SCD, sudden cardiac death.
limitations to non-invasive quantitation of serial stenoses by Doppler echocardiography. While close inspection of the aortic valve leaflets by TEE can be helpful, invasive haemodynamic catheterisation allows accurate delineation of anatomic location and degree of obstruction at each site [24]. Finally, concomitant BAV and HCM has an impact on family screening. Imaging of first degree relatives should assess for the presence of left ventricular hypertrophy, aortic valve morphology and ascending aortic dimension. Ascending aortic dilatation is highly prevalent (32%) among first degree relatives of patients with BAV, even those with tricuspid aortic valves [25]. A strategy of echocardiographic surveillance is what we have adopted.
Study Limitations The reported prevalence of coexistent BAV and HCM in this study may be overestimated from referral bias. This study utilised an electronic echocardiographic database search, thus patients may have been missed if AVR occurred prior to index evaluation or if the diagnoses of BAV or HCM was missed. The combined use of cardiac CT or MR imaging should be considered in future studies to improve identification of patients with combined pathologies. Although this represents the largest studied population of coexistent BAV and HCM, the cohort was still small, despite a large tertiary referral population. The rate of complications could be overestimated due to referral bias. Larger, pooled cohorts with long-term follow-up would be beneficial to validate these findings. Furthermore, comparative outcome analysis between the study population and cohorts with either isolated HCM or isolated BAV were not feasible given the small size of the study cohort with combined conditions and the
wide spectrum of phenotypic heterogeneity seen among patients with isolated HCM and isolated BAV, which would make meaningful comparison challenging, even after adjusting for age and gender.
Conclusions In this study, the prevalence of BAV among patients with HCM was comparable to that of the general population, consistent with disorders of unrelated genetic origin. Surgically-relevant aortopathy and LVOT obstruction were found commonly amongst these patients, necessitating cardiac interventions in a significant proportion of cases. However, long-term survival of patients with coexistent BAV and HCM appeared favourable and similar to an age- and sex-matched control population. Unique management dilemmas exist in patients with coexistent HCM and BAV.
Authors Contributions RP and JBG contributed to study design, data acquisition, analysis, drafting and revision of the manuscript. BJG and SRO contributed to data analysis, drafting and critical revision of the manuscript. All authors approved the final manuscript.
Funding Source This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Disclosures No disclosure. [12]
Conflict of Interest
[13]
None declared.
Acknowledgments The authors would like to thank Mr. David Hodge for his assistance with statistical analysis.
[14]
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Please cite this article in press as: Padang R, et al. Prevalence and Impact of Coexistent Bicuspid Aortic Valve in Hypertrophic Cardiomyopathy. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.01.020