NS is a genetic condition that is frequently associated with congenital heart disease [1]. However, investigation into treatment to resolve systemic obstruction in HOCM has been insufficient. HOCM has initially been treated pharmacologically in symptomatic patients in recent years [2,3]. A classical septal myectomy has been accepted as first-line surgical treatment for both children and adults who are unresponsive to pharmacologic therapy [4-6]. However, in some cases, LVOTO is associated with anomalies of the mitral sub valvular apparatus. Relief of obstruction may be incomplete, or merely temporary if these remain unrecognized and untreated [7].

PTSMA, which is performed using a catheter, has recently emerged as an alternative to surgery in selected patients and is considered comparable to surgical myectomy [8].

The patient was a 13-year-old Japanese male child, who was diagnosed with NS (negative chromosome aberration). He presented with physical malformations and suffered from associated cardiac disorders, namely, pulmonary artery stenosis (PS), HOCM, a patent foramen oval (PFO) and a persistent left superior vena cava (PLSVC). He underwent a percutaneous transluminal pulmonary artery angioplasty (PTPA) at six months of age due to unstable cardiac function. His growth and development progressed normally after the procedure. However, he suffered from progressively worsening dyspnea (NYHA class III), which had been progressively deteriorating. He was forced to discontinue playing with friends at school and complained of tightness in the chest and palpitations on exertion by the age of 13 years. Examination revealed a double apical impulse and a grade 4/6 mid-systolic murmur with a thrill, which are pathognomonic, dynamic auscultatory features of HOCM. He demonstrated the characteristic physical features of NS, which are unique facial dysmorphism, narrow palpebral fissures, brevicollis, a webbed neck, lower auricles, a high palate, cryptorchid testes, umbilical hernia and short stature (height: 142 cm -2.2SD) [1,9,10]. His electrocardiogram (ECG) showed a Left Ventricular Hypertrophy (LVH) and septal Q waves in leads I, aVL, V5 - 6, an inverted T wave in lead V1 and tall T waves in lead V2 - 4. His chest X-ray showed a mild cardiomegaly with a Cardiothoracic Ratio (CTR) of 59%. His echocardiogram showed concentric and marked localized basal septal hypertrophy with a mural thickness of measuring 23 mm, compared to the posterior wall thickness of 10 mm. [Figure 1] His left ventricular ejection fraction (EF) was 70%. There was systolic anterior motion (SAM) with mild MR. The intraventricular pressure gradient between ascending aorta and apical was 149 mmHg. Cardiac MRI showed an accelerated jet flow through the LVOT and late gadolinium enhancement around the LVOT during the post-enhancement phase. He was treated for the condition with propranolol 10 mg, twice daily and cibenzoline 50 mg, three times daily. This did not result in adequate alleviation of his symptoms. A coronary angiogram revealed a large first septal coronary artery, which was amenable to PTSMA. We initially considered performing a surgical septal myectomy, but after taking the localized hypertrophy of the basal septal wall into consideration, we believed the hypertrophy would be adequately treated by performing PTSMA. We also suspected an anatomic limitation due to the hypoplastic features of Noonan Syndrome (body height: 142 cm, body weight: 39 kg), which narrowed the space in which to perform the surgical procedure. This further supported the selection of PTSMA.

Under conscious sedation, we created two artery accesses in the right groin using 6F sheaths and one in the left radial artery using a 4F sheath. Venous access was created in the right groin using a 6F sheath. Next, 5000 IU of heparin were administered via intravenous injection, and then we started the procedure. The difference between ascending aortic pressure (measured using a 6F guide catheter, EBU3.0, Medtronic MN USA) and left ventricular apical pressure (measured using a 4F pigtail catheter, Type MTAKA, Medikit Tokyo Japan) gradient was 43 mmHg at rest during the pre-procedure stage.

Figure 1

The first septal artery was cannulated using a balanced middle weight guide wire (BMW, Abbott Vascular, Santa Clara, CA, USA) and an over-the-wire balloon (Marverick 1.5/9 mm, Boston Scientific, Natick, MA, USA) was positioned in the proximal segment of the first septal artery. The balloon was inflated to a pressure of 4 atm, then the guide wire was withdrawn. Contrast agent (Levovist, Bayer) was infused into the central lumen of the balloon to verify adequate perfusion to hypertrophic myocardium during echocardiography. After 1.3 ml of absolute alcohol was slowly infused into the septal artery vessel (at a rate of 0.3 ml/min), the echocardiogram showed coincident alcoholic shadow enhancement consistent with hypertrophic myocardium. The ECG during this time now showed left bundle branch block (LBBB). After the obstructive myocardium was ablated, we noted a drastic decrease in the pressure gradient between the left ventricular pressure and the aortic pressure, with a final difference of 13 mmHg. The procedure was then concluded.

In the post-procedural period, the level of creatine kinase (CK) MB isoenzyme (max) peaked at 68 IU/L. The LBBB that developed during the procedure disappeared within a half day. The day after procedure, the patient was able to resume all his activities with no limitations, and remarked, ‘My life has changed completely’. During the 10-day in-patient observation period, there were neither documented ventricular arrhythmias nor blocks on Holter ECG, so he was discharged in an asymptomatic state.

However, two years after PTSMA, he again complained of recurrent exertional dyspnea (NYHA class III) and syncope. In Holter ECG multiform premature ventricular contractions (PVCs) and paroxysmal atrial fibrillation (PAF) were detected. Catheter pressure studies showed no remarkable elevation of pressure gradients between aorta and LVOT at rest, although the extra-systolic ventricular provocation triggered PVCs, and the subsequent pressure gradient was significant (9 mmHg at rest, 22 mmHg post-Valsalva overload and 123 mmHg post-PVC). Echocardiogram and Cardiac CT reassessment revealed regressed LVOT hypertrophy, but residual ventricular hypertrophy (20 mm) of the basal anterior septum with a pressure gradient of 26 mmHg and mild MR with an anomalous mitral chorda tendinea that joined the anterolateral papillary muscle to the extruding ventricular septum. [Figure 2] LV contraction was maintained (EF 59.7%), whereas LV end-diastolic volume was reduced (LVEDV 151.3ml).

Figure 2

We therefore suspected that this residual extruding ventricular septum and abnormal chorda caused the obstruction. Concomitant SAM of the anterior mitral leaflet exacerbated MR during exertion. By the age of 15 years, he had developed to a physical size that accommodated open-heart surgery (body height: 158 cm, body weight: 48 kg). We then performed a surgical septal myectomy with resection of the sub valvular apparatus. The operation was performed via a median sternotomy. Standard cardiopulmonary bypass was established with ascending aortic and bicaval cannulation. The persistent left superior vena cava (PLSVC) was surrounded and secured with umbilical tape. The ascending aorta was cross-clamped and cardiac arrest was maintained using intermittent antegrade and retrograde cardioplegia. The procedure involved performing the anterior two thirds of a transverse aortotomy, enabling visualization of the LVOT using a transaortic approach. [Figure 3] We started the classical portion of the resection by making 2 parallel longitudinal incisions in the septum; the first underneath the nadir of the right coronary cusp, and the second underneath the commissure between the right and the left coronary cusps [11,12]. These incisions were connected superiorly with a third horizontal incision 13 mm in length positioned below the aortic valve and a forth horizontal incision 36 mm in length positioned below the aortic valve. This enabled the resection of a deep wedge of septal tissue (18 mm in length). All anomalous chordal structures and fibrous attachments of the mitral leaflets to the intraventricular septum (IVS) were divided. All abnormal chordae attached to the free edge of the mitral leaflet were preserved to prevent flailing leaflets. After the patient was weaned from cardiopulmonary bypass, we performed simultaneous pressure measurement of the left ventricle and aorta, which showed no recordable difference. Intraoperative transesophageal echocardiograms also confirmed no residual pressure gradient, as well as no postoperative SAM.

Figure 3

The patient reported postoperative alleviation of the physical symptoms. Postoperative magnetic resonance imaging (MRI) revealed that extruding ventricular hypertrophy of the basal anterior septum had resected and the accelerated jet flow had diminished. Also LV contraction was maintained (EF 64.9 %) and LV end-diastolic volume was increased (LVEDV 166.9ml). [Figure 3] The postoperative echocardiogram showed that the pressure gradient across the basal anterior septum decreased to 13 mmHg, which corresponded to the disappearance of SAM with mild MR. Histological investigation revealed myxoid degeneration of the anomalous chorda, and myocardial hypertrophy with disarray as well as interstitial fibrosis. Fibrous thickening of the endocardium also observed [Figure 4].

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Figure 4

On postoperative day eight, we implanted an implantable cardioverter defibrillator (ICD), indicated for the primary prevention of fatal ventricular arrhythmia. Finally, he was discharged with significant and permanent improvement of his symptoms and exercise capacity without the recurrence of arrhythmia.

Discussion

Congenital cardiovascular malformations (CCVMs) have been reported in as many as 80% of patients with NS [13,14]. One particular CCVM, hypertrophic cardiomyopathy, appeared in 16% to 30% of all NS cases [15,16]. The characteristic echocardiogram features in patients with HOCM concomitant with NS, compared with other types of HOCM, were asymmetric septal hypertrophy and LVOTO [17]. However, no systemic analysis of the features of the myocardial hypertrophy with NS has been performed from the perspective of evaluating LVOTO for treatment.

On the other hand, there have been reported case investigations of anomalies of the mitral sub valvular apparatus in HOCM adult patients. A report by Kenji M. et al states that anomalous papillary muscles fusion to the ventricular septum and anomalous chordae tendineae are the most common anomalies of the sub valvular apparatus, which can be recognized and diagnosed by intraoperative exposure [7].

We suspected that a mitral sub valvular apparatus were present in this case due to the diminished LV-Volume and exacerbation of symptoms after PTSMA.

Opinions regarding the role of PTSMA in childhood HOCM have varied considerably. However in this case, we choose PTSMA as first-line treatment at the age of 13 years old in consideration of the localized myocardial basal septal hypertrophy and the age-related dysmorphic features characteristic of NS. We later selected an additional surgical myectomy and resection of sub valvular apparatus with ICD implantation once the patient reached 15 years of age, as this would reduce not only the physical symptoms but also the risk of myocardial remodeling caused by intra ventricular pressure overload associated with the fatal ventricular arrhythmia.

In the case of NS with concomitant localized LVOTO, precise outflow evaluations for treatment to relieve obstruction should be achieved.

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