Discussion

Subaortic stenosis is the second most common cause of left ventricular outflow obstruction in children, and it may be isolated or accompany other cardiac anomalies. ^{Reference Friedland-Little, Zampi, Gajarski, Allen, Shaddy, Penny, Cetta and Feltes1} It is more common in males with a male to female ratio of 1.5:1–2.5:1. ^{Reference Friedland-Little, Zampi, Gajarski, Allen, Shaddy, Penny, Cetta and Feltes1} In our study, there was a significant male predominance as previously reported and the male to female ratio was 2.2, 2 and 2.5 in the whole, isolated and CHD group, respectively. Subaortic stenosis is associated with other CHD’s in more than half of the patients. ^{Reference Newfeld, Muster, Paul, Idriss and Riker15,Reference Choi and Sullivan16} The most common additional malformations are ventricular septal defect and coarctation of the aorta with a ratio of 10–48% and 6–20%, respectively. ^{Reference Friedland-Little, Zampi, Gajarski, Allen, Shaddy, Penny, Cetta and Feltes1} Thirty-five patients in our study had CHD and the ratio of CHD was 43.75%. Similar to previous reports, the most common additional malformations in our study were ventricular septal defect (28.75%) and coarctation of the aorta (8.75%). The most common type is the membranous type which accounts for 70–80% of cases. ^{Reference Friedland-Little, Zampi, Gajarski, Allen, Shaddy, Penny, Cetta and Feltes1,Reference Devabhaktuni, Chakfeh, Malik, Pengson, Rana and Ahsan17,Reference Abushaban, Uthaman, Selvan, Al Qbandi, Sharma and Mariappa18} Although 63.7 and 80% of cases in the whole and CHD group had membranous type; the frequency of membranous and fibromuscular type was similar in the isolated group (51.1% versus 48.9%) in our study. The mean age at the time of surgical resection was significantly lower in the CHD group. This is because the patients who underwent surgery for CHD also had subaortic stenosis resection irrespective of the severity of the stenosis.

Aortic insufficiency is an important complication that may develop in 50–70% of these patients over time. ^{Reference Friedland-Little, Zampi, Gajarski, Allen, Shaddy, Penny, Cetta and Feltes1,Reference Devabhaktuni, Chakfeh, Malik, Pengson, Rana and Ahsan17} Unsurprisingly, in our study, the frequency of aortic insufficiency increased from 52.5%, 62.3%, and 40% to 68.75%, 80%, and 54.3% at the last follow-up in the whole, isolated and CHD group, respectively. The association between a higher gradient and aortic insufficiency has been confirmed by the previous studies ^{Reference Abushaban, Uthaman, Selvan, Al Qbandi, Sharma and Mariappa18–Reference Karamlou, Gurofsky and Bojcevski20} . In our study gradient at the time of diagnosis and maximum gradient during follow-up was positively correlated with aortic insufficiency at all times, as previously reported. Besides gradient, mitral-aortic separation and surgery were also positively correlated with aortic insufficiency at the last follow-up. The correlation of gradient and surgery with aortic insufficiency is not surprising, as one of the proposed mechanisms of aortic insufficiency is long-term exposure to high-velocity jet. The degree of aortic insufficiency was similar between the groups, but when aortic insufficiency was compared as none and present, the number of patients with aortic insufficiency was significantly higher in the isolated group at the last follow-up (p = 0.026). We think that this may be due to two reasons: The primary disease of the patients in CHD may also cause aortic insufficiency; the patients in the CHD group had surgical resection earlier than the isolated group and the mean maximum gradient of the CHD group was significantly lower. Brauner et al ^{Reference Brauner, Laks, Drinkwater, Shvarts, Eghbali and Galindo21} and Somerville et al ^{Reference Somerville, Stone and Ross22} also reported that early surgical intervention can be beneficial in preventing progressive damage to the aortic valve.

Subaortic stenosis constitutes 20% of obstructions that require intervention in children. ^{Reference Masse, Shar, Brown, Keswani, Grande-Allen and Sucosky14} The treatment of choice is surgical resection. The risk of early mortality of surgery is very low, but subaortic stenosis reoccurs in 20–30% of the patients after successful surgical resection. ^{Reference Friedland-Little, Zampi, Gajarski, Allen, Shaddy, Penny, Cetta and Feltes1,Reference Tal, Golender, Rechtman, Tidhar and Erez3,Reference Vogt, Dische, Rupprath, de Vivie, Kotthoff and Kececioglu8} Uysal et al ^{Reference Uysal, Bostan, Signak, Semizel and Cil2} reported that 64.6% of 66 children with subaortic stenosis underwent surgery and only 1 of the15 patients with recurrence required a second surgery. Tal et al ^{Reference Tal, Golender, Rechtman, Tidhar and Erez3} reported that 26 of 34 patients with isolated subaortic stenosis underwent surgery and only 3 (12%) patients required reoperation. Two of these patients in this study were reoperated because of progressive aortic insufficiency. Binsamalah et al ^{Reference Binsalamah, Spigel and Zhu23} reported that 12 (14%) of 84 patients who underwent resection of isolated subaortic stenosis required reoperation and one patient required reoperation twice at a median follow-up of 9.3 years. The median time to the first operation was 4.6 years. In our study, a total of 35 (43.7%) patients underwent surgery for subaortic stenosis. 16 (45.7%) and 19 (42.2%) patients in the CHD and isolated group underwent surgical resection. Although the rate of surgery was similar between the groups, 12 of 16 patients with CHD had surgical resection as they underwent surgery for CHD. All the patients in the isolated group underwent surgery with the indications described above but none of them underwent surgery or reoperation with the indication of progressive aortic insufficiency. Twenty-six of the patients in the isolated group did not undergo surgery. The distribution of aortic insufficiency in this subgroup at the time of diagnosis and the last follow-up respectively were as follows: None: 11 versus 7, Trivial: 5 versus 6, Mild: 10 versus 13. None of these patients had moderate or severe aortic regurgitation. We think that progression of aortic insufficiency in patients with lower gradients is slow. Therefore clinicians should feel safer in this group of patients and should prefer close follow-up instead of early surgery. The rate of reoperation was 14% at a mean follow-up of 84.8 ± 53.3 months and all the reoperated patients were in the isolated group. We believe that this difference is because most of the patients in the CHD group had surgical resection irrespective of the severity of the stenosis as they underwent surgery for CHD. Although the ratio of patients who underwent surgery was higher in the fibromuscular group than the membranous group, there was no significant difference in means of operation and reoperation between the fibromuscular and membranous groups.

Subaortic stenosis may cause progressive obstruction in children but the rate of progression varies among patients. Several factors have been opposed in the development of subaortic stenosis but factors leading to rapid progression are still unclear. ^{Reference Friedland-Little, Zampi, Gajarski, Allen, Shaddy, Penny, Cetta and Feltes1,Reference Tutar, Atalay, Turkay, Gumus and Imamoglu4–Reference Mulla and Siddiqui7} Surgical resection is the ultimate treatment for the relief of obstruction. The most and well-known predictor of surgery is the gradient across left ventricular outflow tract. ^{Reference Friedland-Little, Zampi, Gajarski, Allen, Shaddy, Penny, Cetta and Feltes1,Reference Mulla and Siddiqui7,Reference Brauner, Laks, Drinkwater, Shvarts, Eghbali and Galindo21,Reference Carlson, Pickard and Gauvreau24} Aortic and mitral annulus z score, longer left ventricular ejection time, the distance of the membrane to the aorta during systole, and other left-sided lesions have been proposed to correlate with surgery. ^{Reference Karamlou, Gurofsky and Bojcevski20,Reference Carlson, Pickard and Gauvreau24} In our study, the gradient at the time of diagnosis and the maximum gradient during follow-up were the only predictors of surgery in both groups. The role of abnormalities in left ventricular outflow architecture in the development of subaortic stenosis has been previously shown. A steeper aortoseptal angle and wider mitral-aortic separation are the most strongly proposed anomalies. ^{Reference Tutar, Atalay, Turkay, Gumus and Imamoglu4,Reference Kalfa, Ghez, Kreitmann and Metras25} In our study, mitral-aortic valve separation was positively correlated with surgery and reoperation just in the isolated group but in contrast to previous reports, we did not find any correlation between the aortoseptal angle and surgery. Although similar to previous studies we found a positive correlation between mitral-aortic valve separation and surgery/reoperation, this result must be interpreted carefully as in our study mitral-aortic valve separation was not indexed to body surface area. Tutar et al ^{Reference Tutar, Atalay, Turkay, Gumus and Imamoglu4} and Kalfa et al ^{Reference Kalfa, Ghez, Kreitmann and Metras25} both used an aortoseptal angle of <130° as a cut-off value and Tutar et al ^{Reference Tutar, Atalay, Turkay, Gumus and Imamoglu4} also reported that an aortoseptal angle of <130° is a highly sensitive marker for possible development of subaortic stenosis. We failed to show any correlation of aortoseptal angle with surgery and reoperation even when we used 130° as a cut-off value in patients who underwent surgery for subaortic stenosis.

Although inadequate resection may be a factor for reoperation, reoperation is required in 15–20% of the cases with subaortic stenosis despite successful resection. ^{Reference Devabhaktuni, Chakfeh, Malik, Pengson, Rana and Ahsan17} Increased peak gradient and early age at the time of diagnosis, tunnel-type stenosis, distance <5 mm between the membrane and aortic valve, peak Doppler gradient of >60 mmHg, concomitant cardiovascular defects (esp. coarctation of the aorta), younger age at initial surgery are risk factors for recurrence and reoperation. ^{Reference Friedland-Little, Zampi, Gajarski, Allen, Shaddy, Penny, Cetta and Feltes1,Reference Geva, McMahon, Gauvreau, Mohammed, del Nido and Geva9,Reference Pickard, Geva, Gauvreau, del Nido and Geva10,Reference Abushaban, Uthaman, Selvan, Al Qbandi, Sharma and Mariappa18} Abushaban et al ^{Reference Abushaban, Uthaman, Selvan, Al Qbandi, Sharma and Mariappa18} reported that age <6 years at initial repair to be an independent predictor of reoperation. In our study, all patients who were reoperated had a peak gradient of <25 mmHg after surgery except one patient who had a peak gradient of 50 mmHg. The earliest reoperation was 73 months after the first surgery in a patient with a post-operative gradient of 15 mmHg. Only one of these patients had the first operation at <6 years of age. None of the seven patients with coarctation of the aorta had reoperation. In our study, the maximum gradient during follow-up, the gradient at the time of diagnosis and catheter angiography were the most important factors for reoperation, as expected.

Aortoseptal angle, mitral-aortic separation and distance of membrane to the aorta are known to correlate with the development of subaortic stenosis, surgery and reoperation. In our study, among these parameters, only mitral-aortic separation correlated with surgery and reoperation in the isolated group. Contradictory to the previous reports, we failed to show any correlation of aortoseptal angle and distance of membrane to the aorta with reoperation. Aortoseptal angle just positively correlated with the gradient at the time of the diagnosis and after surgery.