Article ID: CJ-16-0945
A46-year-old man was referred to Ehime University Hospital for the treatment of refractory heart failure. On admission, blood pressure was 98/68 mmHg and heart rate was 92 beats/minute. A harsh crescendo-decrescendo systolic murmur was heard at the second right intercostal space. Electrocardiogram showed left ventricular (LV) hypertrophy with normal QRS complexes. On transthoracic echocardiography the LV ejection fraction (LVEF) was 33% with severe calcification of the aortic valve, and the LV end-diastolic diameter was enlarged to up to 65 mm. LV wall thickness was approximately 9 mm and LV mass index was 139 g/m2. Transmitral flow pattern was restrictive with increased E/A ratio of 4.3. The peak and mean pressure gradients across the aortic valve were 38 mmHg and 27 mmHg, respectively. Except for aortic stenosis, there was no evidence of any other valvular disease. Transesophageal echocardiography clearly demonstrated a unicuspid, unicommissural aortic valve with 2 calcified raphes (Figure 1A; Movie S1). A commissure attachment between the left coronary cusp and non-coronary cusp was observed. Cine cardiac magnetic resonance imaging (MRI) showed LV eccentric hypertrophy with diffuse hypokinesis (Movie S2). The end-diastolic volume assessed on cardiac MRI was 293 mL, indicating LV dilatation. In addition, late gadolinium enhancement was seen in the mid-wall portion of the interventricular septum (Figure 1B,C). To distinguish between true and pseudo-severe aortic stenosis, dobutamine stress echocardiography was performed. During the infusion of 10 µg/min/kg dobutamine, heart rate increased from 78 to 92 beats/min and blood pressure changed from 88/56 to 96/58 mmHg. The peak and mean pressure gradients across the aortic valve markedly increased to up to 100 mmHg and 61 mmHg, respectively. The aortic valve area according to continuity equation was 0.89 cm2. Thus, we concluded that the severe aortic stenosis was true. Accordingly, aortic valve replacement (AVR) with a 25-mm Epic valve was performed (Figure 1D). The removed aortic valve had a commissure attachment between the left coronary cusp and non-coronary cusp (Figure 1E) and the calcified raphes corresponded to the transesophageal echocardiography, confirming a unicuspid, unicommissural aortic valve with 2 calcified raphes. LV myocardial biopsy was performed during surgery, and the pathology was compatible with dilated cardiomyopathy. Although the postoperative course was uneventful, LVEF 4 months after AVR remained relatively unchanged (43%).
(A) Transesophageal echocardiography showing a unicuspid, unicommissural aortic valve with 2 calcified raphes. (B,C) Cardiac magnetic resonance imaging. Late gadolinium enhancement was seen in the mid-wall portion (arrows). (D) Intraoperative finding of the aortic valve. A slit-shaped unicommissural aortic valve was detected. (E) The removed aortic valve had a commissure attachment (asterisk) between the left coronary cusp (LCC) and non-coronary cusp (NCC). Two calcified raphes were also detected. RCC, right coronary cusp.
Unicuspid aortic valve is a very rare congenital anomaly, with an estimated prevalence of 0.02% in the adult population.1 Most patients with unicuspid aortic valves develop severe aortic stenosis and require aortic valve replacement in middle age. Mookadam et al reported that of 231 adult patients with unicuspid aortic valve (mean age, 42 years), 202 (87%) underwent some form of operation for unicuspid aortic valve.2 Generally, aortic stenosis presents with concentric hypertrophy because of LV pressure overload, resulting in the reduction of the LV dimension. Obvious LV dilatation and eccentric hypertrophy, however, were combined in the present case. We considered the association of underlying dilated cardiomyopathy and carried out genetic screening using the illumina TruSight Cardio sequencing kit. This test exhaustively screened the coding sequences of 172 genes previously implicated in inherited cardiac diseases. Among them, 59 genes have been reported to be associated with dilated cardiomyopathy. In the present case, on genetic sequencing the patient was heterozygous for 2 rare variants in ACTN2 (c.2113G>A, Ala705Thr) and in RYR2 (c.10190G>A, Arg3397His). Both mutations were confirmed on Sanger sequencing (Figure 2). On analysis with PolyPhen-2, the ACTN2 (Ala705Thr) and RYR2 (Arg3397His) mutations were classified as possibly damaging (score, 0.61) and probably damaging (score, 0.961), respectively. ACTN2 is an important component of the sarcomere Z-disc, in which its primary function is to anchor and cross-link actin filaments.3 ACTN2 influences LV geometry and contraction.4 In contrast, RYR2 plays a crucial role in cardiac excitation–contraction coupling by mediating calcium release from the sarcoplasmic reticulum, which is required for myocardial contraction. Both were previously shown to be associated with dilated cardiomyopathy.4–6 Taken together, this might explain the eccentric hypertrophy in the present case. We have thus reported a case of maladaptive response to pressure overload (not concentric, but eccentric LV hypertrophy) in a patient with severe aortic stenosis caused by unicuspid aortic valve. Although further molecular and functional studies are needed to clarify whether these rare variants are pathogenic, genetic analysis might be a useful approach to clarify the mechanism of uncommon LV geometry in patients with aortic stenosis.
Sanger sequencing of the present gene mutations. Arrows, mutation sites.
This work was supported by a Grant-in-Aid for Scientific Research (C) (JSPS KAKENHI Grant Number 26461072).
The authors declare no conflict of interest.
Supplementary File 1
Movie S1. Transesophageal echocardiography showing a unicuspid, unicommissural aortic valve.
Supplementary File 2
Movie S2. Cardiac magnetic resonance imaging showing left ventricular eccentric hypertrophy with diffuse hypokinesis.
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-16-0945
