Clinical features of quadricuspid aortic valve in middle‐aged and elderly patients: Insights from a regional study

Quadricuspid aortic valve (QAV) is a rare congenital disease. The clinical characteristics of this disease remain unclear except for those in relatively young patients reported from tertiary referral hospitals. The aim of this study was to determine the clinical features of QAV in a regional population.

of cases, while only 16% of these valves functioned normally. 8Previous reports from a high-volume tertiary heart center showed that most patients with QAV underwent aortic valve surgery around their thirties. 4wever, these data could have referral bias, and the clinical features of this disease might be different in regional populations.There are few reports other than case reports of QAV from non-tertiary centers.Recent technological advancements in echocardiography could contribute to an increased detection rate of QAV. 9 The aim of this study was to clarify the clinical features of QAV after middle age in a regional medical institute.

Subjects
We retrospectively investigated consecutive patients who under- The clinical course, including cardiac events or history of cardiac surgeries, was obtained from medical records or through telephone contact with the patients themselves or their referring relatives.
The study protocol was approved by the Ethical Review Board of Kochi Medical School, Kochi University (approval number: 2021-145).

Echocardiography
Echocardiographic images were typically obtained in either the supine or left lateral decubitus positions.We reviewed all patients' echocardiographic reports and reviewed the images in cases where the report indicated or suspected the presence of QAV.The QAV diagnosis was confirmed in each case by at least two independent observers (sonographers and/or cardiologists).
The echocardiographic definition of QAV included a characteristic "X" in diastole and freely opening cusps in a rectangular configuration in systole. 5,10om echocardiographic short-axis images, QAVs were classified into seven subtypes, lettered A to G, based on leaflet size and distribution as reported by Hurwitz and Roberts. 3 QAVs were also classified into four subtypes, numbered I to IV, based on location of the supernumerary valve according to the classification of Nakamura. 11 In our institute, we usually performed echocardiography according to the American Society of Echocardiology guidelines. 12Left ventricular diastolic dimension (LVDd), left ventricular systolic dimension (LVDs), and left atrium (LA) dimension (LAD) were measured from Mmode and 2-D images obtained from parasternal long-axis views, and LV ejection fraction (LVEF) and LA volume (LAV) were measured by the modified Simpson's method (method of discs).Severity of valvular disease was graded in accordance with the American Society of Echocardiology guidelines. 12

Statistical analysis
Data are expressed as means ± SD for normally distributed variables and as medians with interquartile range (IQR) or range for non-normally distributed data.Categorical data are expressed as numbers (percentages).Statistical analysis was performed using IBM SPSS Statistics, version 28.0 (IBM Corp., Armonk, NY).
The characteristics of those eight QAV patients are summarized in Table 1.All of the eight patients were East Asian (Japanese).The median age of those patients was 65 years (range, 47 to 91 years) and 4 (50%) of the patients were males.The reasons for performing TTE in those patients included non-cardiac preoperative screening (n = 4), evaluation of cardiac murmur (n = 1), and assessment of the severity of AR (n = 3)

Echocardiographic findings in the patients
The echocardiographic findings of the eight patients are presented in Tables 1 and 2. According to Hurwits and Roberts classification of QAV, two cases were classified as type A (four equal-sized cusps), four cases were classified as type B (three equal-sized cusps and one small cusp), and two cases were classified as type C (two equal-sized larger cusps and two equal-sized smaller cusps).Dilatation of the aortic root can influence aortic insufficiency in congenital aortic valves.We measured the aortic root diameters of our patients, as shown in Table 2.We found that one patient had a dilated ascending aorta; however, this patient (Case 3 in Table 2) did not present with significant aortic regurgitation.

The ages at interventions
Tsang et al. reported that the average age at diagnosis for eight patients with QAV who underwent an aortic valve operation was 34.8 ± 21.6 years, while the average age at diagnosis for 42 patients who did not receive an aortic valve operation was 45.2 ± 21.6 years. 4These data could reflect referral bias from a high-volume tertiary heart center.
Indeed, among patients undergoing AVR, the incidence of QAV ranges from 0.48% to 1.46%, which is 10 to 50-times higher than the incidence shown in autopsy or echocardiography studies. 6,7In our cohort, only two middle-aged patients with severe AR at the time of referral required aortic valve surgery.Their ages at the time of surgery were 61 and 47 years.

Subtypes for interventions
Consistent with previous reports indicating that approximately 85% of QAVs are of type A, B, or C, 13 all of the patients in this study were classified into these three types, including four patients with type B QAV.
One patient with type A QAV and one patient with type C QAV in this study required AVR in this study.
Feldman et al. found that AR was more common in patients with a smaller accessory cusp (type B) and suggested that unequal stress distribution and abnormal leaflet coaptation in this type may result in progressive AR. 7 Conversely, with cusps of nearly equal areas (type A), transvalvular forces are equally distributed, potentially limiting progression.On the other hand, Tsang et al. reported that the subtypes of QAV were not associated with valve insufficiency. 4 It remains unclear whether these specific subtypes predispose patients to more severe AR or whether severe AR reflects the predominance of these subtypes in patients with QAV.We speculate that a diagnosis of QAV after middle age without severe valve insufficiency indicates a tolerance to the condition from birth regardless of the QAV type.These patients might be able to live their lives without intervention for their aortic valve. 14In fact, one patient diagnosed with type B QAV at the age of 91 years lived a long life without cardiac events and died of pneumonia at the age of 94 years.
The findings of this study suggest a potential reevaluation of QAV, indicating that it might be considered a less severe congenital anomaly than previously thought in the general population.

Limitations
There are several limitations in this study.Firstly, this study was conducted at a single institute with a small sample size, which might introduce selection bias, as our institute is a regional university hospital.
Secondly, a notable constraint of this study is the method of diagnosing QAV.For the majority of the patients, the diagnosis was based on TTE and validated by at least two observers.However, more definitive diagnostic modalities such as TEE, cardiac MRI, surgical pathology, or autopsy were not employed in confirming QAV for 6 out of 8 patients.
This reliance on TTE without further confirmation through these additional methods could be considered a major limitation, as it might have impacted the accuracy and reliability of the QAV diagnoses.Thirdly, we reviewed all 25 340 echocardiographic reports, but not all patients' echocardiographic images.There is a possibility that we might have overlooked QAV in some patients.Moreover, we sometimes encountered poor echocardiographic visualization in the short axis view at the aortic valve level.These factors represent significant limitations of our study, potentially leading to both underestimation and overestimation of the prevalence of QAV.Fourthly, we did not do a genetic analysis of QAV patients since this study was retrospective nature.QAV could be associated with several genetic syndromes including Noonan or William. 15If patients with QAV had genetic syndrome, the clinical course might be changed.However, we reviewed medical record of our QAV patients and found that no patients have clinical features of these genetic diseases.Finally, the follow-up period was relatively short.A longer follow-up period might reveal changes in the patients' clinical courses.

CONCLUSIONS
QAV was rare in our cohort.For middle-aged or older patients with QAV and without severe valve insufficiency, there is a potential that they might have relatively stable clinical outcomes.However, this may vary depending on the individual condition of each patient and further research is required for a better understanding of the long-term outcomes.

ACKNOWLEDGMENTS
transthoracic echocardiography (TTE) at Kochi Medical School Hospital, located in a rural area of Japan, between April 2008 and December 2023.After excluding any duplicates, 30 823 patients were screened.It is possible that patients with a genetic syndrome or severe valve insufficiency might have already passed away or undergone valve interventions during their childhood or youth.To concentrate on middle-aged and elderly patients, we excluded those under 45 years old.Consequently, 25 340 patients were included in the study.

Figure 1 and
Videos S1-S3 show representative cases of types A, B, and C, respectively.Other cardiac anomalies included and right-sided aortic arch in one patient.Two patients (Cases 6 and 8 in the tables) exhibited severe AR, while the other patients showed AR that was either moderate or less.No patients presented aortic stenosis (AS), except for one patient with mild AS.With the exception of one patient (Case 6), all of the patients showed normal left ventricular systolic function.

A
Takiishi, Y Baba, and T Kubo conceived the idea for the study and planned the investigations.Y Baba, Y Ochi, N Yamasaki, and H Kitaoka undertook clinical investigations of patients.A Takiishi, M Hotta, N Okazaki, Y Yoshinaga, S Miyamoto, D Hirakawa, J Kawaguchi, Y Ochi, and Y Baba examined echocardiography.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
TA B L E 1 characteristics of the patients in the present study.