Sinus of Valsalva aneurysm (SVA) is a rare cardiovascular anomaly marked by abnormal dilation of one of the aortic sinuses—most frequently the right coronary sinus—due to congenital or acquired wall weakness. Congenital SVAs originate from developmental defects at the junction of the aortic media and annulus fibrosus, with an incidence of approximately 0.09%, and show male and Asian predominance [1,2]. Acquired forms may result from infective endocarditis, trauma, connective tissue disorders (e.g., Marfan syndrome), or previous aortic valve surgery [3,4].

Unruptured SVAs are often asymptomatic but may present with exertional dyspnoea, chest pain, or arrhythmias if they enlarge and compress adjacent cardiac structures [4]. Rupture typically leads to an aorto-cardiac fistula and left-to-right shunt, manifesting as acute chest pain, heart failure, and a continuous murmur. If untreated, the prognosis is poor, with mean survival reported at 3–4 years [5].

The rupture site correlates with the sinus of origin. Right coronary sinus (RCS) aneurysms account for 65–85% and usually rupture into the right ventricle or outflow tract [1,6]. Non-coronary sinus aneurysms more often rupture into the right atrium, while left coronary sinus (LCS) aneurysms—rare (<5%)—may rupture into the left atrium, pulmonary artery, or superior vena cava [1,6].

Associated cardiac anomalies significantly influence clinical course and surgical planning. Ventricular septal defects (VSDs) occur in 20–45% of RSVA cases due to shared embryologic defects [3,5]. Moderate-to-severe aortic regurgitation (AR) occurs in up to 30%, resulting from cusp distortion or annular dilation [3,5]. Tricuspid regurgitation, pulmonary hypertension, and arrhythmias may also be present. Infective endocarditis plays a key role in acquired SVAs and complicates surgery due to tissue friability [3].

Echocardiography remains the initial diagnostic modality, providing visualization of the aneurysm, shunt jet, and valvular lesions. Transoesophageal echocardiography (TEE) offers higher resolution for small or atypical SVAs [1]. Computed Tomography angiography (CTA) and Magnetic Resonance Imaging (MRI) provide detailed anatomical mapping, crucial for surgical planning in complex ruptures. In our series, CT confirmed a rare left coronary sinus (LCS) -to-superior vena cava (SVC) rupture and delineated the unruptured case. Cardiac catheterization is used selectively for anatomical clarification or attempted device closure [7,8].

Surgical repair is the mainstay of RSVA management. Since the first successful repair using cardiopulmonary bypass in the 1950s [9], outcomes have improved significantly. Surgery involves closure of the aneurysmal tract via direct suture or, more commonly, patch repair using pericardium, Dacron, or Polytetrafluoroethylene (PTFE). Patch closure has a lower recurrence risk and is the current standard [1,10]. Associated defects (e.g., VSD, valve pathology) are corrected concurrently.

Transcatheter closure has emerged as an alternative in select anatomies. First reported in 1994 [11], it is generally reserved for isolated RSVA without associated lesions. Risks include device embolization and incomplete closure. In our series, two patients had failed device attempts requiring surgical rescue. Surgery remains the gold standard in most RSVA cases.

This report presents our single-centre experience with surgical management of seven SVA cases, discussing presentation, operative details, and outcomes in current literature.

Study Design and Patients: This retrospective case series includes seven patients with SVA who underwent surgical treatment at a tertiary cardiothoracic centre in New Delhi, India, from 2019 to 2024. Patients were identified from surgical and echocardiographic databases. In all cases, the diagnosis was confirmed via echocardiography and CTA, with catheter angiography used selectively. Six patients had ruptured SVA; one had an unruptured aneurysm.

Surgical Technique:

All patients underwent open-heart surgery through median sternotomy with cardiopulmonary bypass and cardioplegic arrest. The surgical approach (transaortic alone vs. dual incision) was individualized based on the rupture site and associated anomalies. The aneurysm was repaired using a patch technique—either PTFE, Dacron, or bovine pericardium. Associated lesions such as VSD or significant valvular regurgitation were addressed concurrently. Aortic or mitral valve replacements were performed with mechanical prostheses. Two cases had initial transcatheter interventions, one had failed transcatheter closure, and the other had embolization of device.

Data Collection:

Demographics, presenting symptoms, imaging findings, intraoperative details (patch type, cross-clamp time, valve procedures), and postoperative outcomes were recorded. Intensive care unit and hospital stay duration, complications (e.g., residual shunt, heart block), and follow-up data (Survival, symptoms, reintervention) were analysed. Follow-up was obtained through clinic visits or phone interviews.

Baseline Characteristics

Seven patients (6 males and one female; mean age 25.1 + 5.1 years, range 18–32) underwent surgical repair for sinus of Valsalva aneurysm (SVA), including six with ruptured SVA (RSVA) and one unruptured case. Dyspnoea on exertion was the most common presenting symptom (6/7), followed by palpitations (4/7); two reported syncope or presyncope, and one presented with haemoptysis and hematemesis due to pulmonary venous hypertension. The unruptured case manifested with exertional fatigue and severe aortic and mitral regurgitation. Notable comorbidities included healed infective endocarditis (n=1) and chronic liver disease with past pulmonary tuberculosis (n=1). These comorbidities potentially increased operative complexity.

Preoperative Evaluation

Transthoracic echocardiography (TTE) was diagnostic in all cases, revealing high-velocity left-to-right shunts in RSVA. Rupture sites included the right ventricle (n=3), right ventricular outflow tract (n=2), and superior vena cava (n=1). Four patients had associated VSDs (4–25 mm), and one was later identified as a windsock aneurysm. Moderate or greater aortic regurgitation (AR) was noted in four patients, and two had pulmonary hypertension with mild tricuspid regurgitation. Computed tomography angiography (CTA) was performed in four cases to delineate complex anatomy—one showing a rare LCS aneurysm rupturing into the SVC, another with an unruptured RCS aneurysm extending into the septum with Bivalvular regurgitation. Cardiac catheterization in two patients confirmed normal coronary anatomy and hemodynamics.

Table 1: Patient Characteristics

Table 1. Summary of Patient Cases (SVA = sinus of Valsalva aneurysm; RSOV = ruptured sinus of Valsalva; LCS = left coronary sinus; RCS = right coronary sinus; RV = right ventricle; RVOT = right ventricular outflow tract; SVC = superior vena cava; VSD = ventricular septal defect; AR = aortic regurgitation; AVR = aortic valve replacement; MVR = mitral valve replacement; PTFE = polytetrafluoroethylene)

Figure 1.
Pie chart showing the origin of the sinus of Valsalva aneurysm in the 7 cases. RCS = right coronary sinus (majority in our series, 6 cases); LCS = left coronary sinus (1 case); NCS = non-coronary sinus (0 cases). This distribution is consistent with most literature reports, in which RCS is the most common origin [1].

Figure 2.
Rupture site distribution among our 7 cases (including the unruptured case). The majority of all SVAs (3/7) (42.8%) ruptured into the right ventricle. Two cases (2/7) (28.5%) ruptured in the right ventricular outflow tract (RVOT). One case (14%) had an unusual rupture into the superior vena cava (SVC). One aneurysm remained unruptured (14%). No ruptures into the right atrium occurred in this series, which is an atypical finding compared to broader statistics [1].

Individual Case Summaries

Case 1 Left Sinus of Valsalva Aneurysm Rupturing into the SVC Modified Sakakibara Type V

A 23-year-old female presented with a 3-year history of exertional dyspnoea, 2 years of palpitations, and recent syncope with blurred vision and intermittent chest discomfort. She was hemodynamically stable with a continuous murmur and diastolic accentuation along the right sternal border. Transthoracic echocardiography suggested a 3–4 mm left-to-right shunt from the left coronary sinus to the left atrium. Aortic root angiography raised suspicion of a coronary cameral fistula from the left main artery to the superior vena cava (SVC), which was clarified by CT angiography revealing a saccular aneurysm from the left coronary sinus with a bifurcated tract draining into the SVC; the left circumflex artery was attenuated, likely due to flow diversion. Surgery via median sternotomy and cardiopulmonary bypass confirmed a palpable thrill at the SVC–right atrial junction. A dual-chamber approach was used: the aortic orifice near the left coronary ostium was closed with a PTFE patch, and the SVC openings were sealed with an intraluminal patch. Postoperative echocardiography showed complete closure. The patient recovered uneventfully and was discharged on day 7. At 6-year follow-up, she remained asymptomatic with normal cardiac function and no recurrence. This case, previously reported as the first known instance of the left sinus of Valsalva aneurysm rupturing into the SVC [16], is now updated with detailed operative and long-term outcome data.

Case 2: RSVA with Device Embolization into Left Pulmonary Artery

A 25-year-old male with chronic liver disease was referred urgently after failed transcatheter closure of a ruptured sinus of Valsalva aneurysm (RSVA). The aneurysm originated from the right coronary sinus (RCS) and had ruptured into the right ventricle (RV) Sakakibara type I. An Amplatzer device had embolized into the left pulmonary artery during the attempted closure. He presented with NYHA Class III dyspnoea, orthopnoea, oedema, and palpitations for 6 weeks. TTE showed a 5 mm windsock-like RSVA from RCS to RV with mild aortic and tricuspid regurgitation, moderate pulmonary hypertension, and preserved ejection fraction (~55–60%). The embolized device was visualized in the left pulmonary artery. Surgery was performed via median sternotomy. The RSVA was closed using a PTFE patch via an aortic approach, and the device was retrieved through a separate pulmonary arteriotomy. The aortic valve was intact and required no intervention. The postoperative course was uneventful. The patient was discharged on day 8. At 2.5 years of follow-up, he was asymptomatic with no residual shunt or complications on echocardiography.

Case 3: RSVA with VSD and Early Postoperative Aortic Regurgitation Requiring Reoperation

An 18-year-old male presented with 6 weeks of exertional dyspnoea. TTE revealed an RSVA from the right coronary sinus (RCS) to the right ventricle (RV), accompanied by a small subaortic VSD and mild AR. On examination, he had a continuous murmur at the mid-sternal border. CT imaging confirmed a 12×17 mm RSVA projecting into the RVOT (Sakakibara Type I). (figure 3)

Figure 3: CT showing ruptured right coronary sinus to RVOT

Surgical repair was attempted after initial consideration for device closure was abandoned as the device was not properly placed due to severe AR. Transaortic approach was used to close both RSVA and the 4–5 mm VSD using PTFE patches. Intraoperative TEE showed mild AR. On day 1 patient was extubated and TTE reviled moderate eccentric AR. Given the risk of progressive heart failure, reoperation was performed on postoperative day 1. The aortic valve was replaced with a 23 mm St. Jude mechanical prosthesis. The previously placed patch was intact. The patient recovered uneventfully and was discharged on day 11 from initial surgery on oral anticoagulation. At a 2-year follow-up, he remained NYHA Class I with a well-functioning prosthetic valve and no residual shunt.

Case 4: RSVA Post-Endocarditis with Subaortic VSD and Residual Shunt

A 32-year-old male with a history of treated infective endocarditis of the right coronary cusp presented with fatigue, dyspnoea, and intermittent fever. He had comorbidities, including chronic liver disease, CKD, splenomegaly, and past pulmonary TB. Transthoracic echocardiography revealed a 23–25 mm RSVA from the right coronary sinus (RCS) into the right ventricular outflow tract (RVOT), a 10×9 mm residual vegetation on the RCS, moderate eccentric aortic regurgitation (AR), and a left-to-right shunt. Intraoperatively, a subaortic VSD was noted, likely congenital. After a brief delay for renal optimization, he underwent patch repair of the RSVA via aortotomy and VSD closure via right atriotomy, followed by aortic valve replacement with a 19 mm St. Jude mechanical prosthesis due to persistent AR and friable tissue. Postoperative TTE confirmed a well-functioning repair with a small (2 mm) residual shunt from RCS to RV managed conservatively. He was discharged on day 7 and remained asymptomatic at the 21-month follow-up with a stable shunt and well-functioning valve.

Case 5: Acute RSVA with Severe AR and VSD Requiring AVR

A 30-year-old male presented with acute decompensated heart failure (NYHA Class IV) and a 3-year history of exertional dyspnoea that worsened in the preceding 24 hours. Examination revealed tachypnoea, BP 104/66 mmHg, and a continuous murmur with a palpable thrill at the apex. TTE demonstrated an RSVA from the RCS to RV, a small outlet-type VSD, severe AR, and a dilated, mildly hypokinetic LV (EF ~45%). Cardiac catheterization confirmed the RSVA and ruled out coronary artery disease. After medical stabilization, urgent surgery was performed via Aorta. RSVA and VSD were closed with PTFE patches, and the heavily calcified tricuspid aortic valve was replaced with a 21 mm St. Jude mechanical prosthesis. Intraoperative TEE confirmed successful repair with a well-seated valve and trivial paravalvular leak. Recovery was uneventful, and the patient was discharged on postoperative day 7. At 5 years and 4 months follow-up, he remained stable in NYHA Class I–II with improved LV function (EF ~50%) and a normally functioning mechanical valve.

Case 6: RSVA with Subaortic VSD Presenting Atypically with Haemoptysis

A 20-year-old male presented with 2 months of intermittent haemoptysis and hematemesis, along with mild exertional dyspnoea. Examination revealed stable vitals and a continuous murmur at the left lower sternal border. TTE showed an RSVA from the right coronary sinus (RCS) to the right ventricle (RV), with a high-velocity restrictive shunt (peak gradient ~120 mmHg), marked LA and LV dilation, but a structurally normal aortic valve. Surgery revealed a 10×15 mm subaortic VSD beneath the right coronary cusp in addition to the RSVA. Both defects were repaired through Aorta, the VSD was closed with a Dacron patch, and the RSVA was closed with a PTFE patch reinforced with pledgeted sutures. The native aortic valve was preserved. Postoperative echocardiography showed complete closure with normalized chamber dimensions and no AR. Haemoptysis resolved postoperatively, likely due to decreased pulmonary venous pressures. Recovery was uneventful, and at 1 year and 7 months follow-up, the patient remained in NYHA Class I with no residual defects.

Case 7: Unruptured Right Sinus Aneurysm with Bivalvular Disease Requiring Dual Valve Replacement

A 28-year-old male with NYHA Class II dyspnoea and occasional cough was found to have severe aortic and mitral regurgitation, with murmurs on clinical exam but no continuous murmur suggestive of RSVA. TTE suggested an ascending aortic dissection, but CT angiography confirmed a large unruptured saccular aneurysm (2.4 × 5.0 × 4.3 cm) originating from the right coronary sinus (RCS) and projecting into the interventricular septum without rupture. The aneurysm caused right coronary cusp prolapse with eccentric AR and anterior mitral leaflet distortion leading to MR. EF was 50–55%, with a dilated aortic root (45 mm) and annulus (29 mm). Intraoperatively, a 12 mm orifice was identified in the RCS. A bovine pericardial patch was used to exclude the aneurysm from systemic pressure. The mitral valve, exhibiting a flail A2 scallop, was replaced with a 29 mm Carbomedics mechanical valve; the aortic valve was replaced with a 21 mm St. Jude mechanical prosthesis. Postoperative recovery was uneventful. At the 12-month follow-up, the patient remained asymptomatic with well-functioning dual prosthetic valves, normalized LV dimensions, and improved EF (45–50%)

Figure 4:
Sagittal CTA reconstruction showing a large saccular sinus of Valsalva aneurysm arising from the right coronary sinus. The aneurysm measures 2.4 × 5.0 × 4.3 cm (anteroposterior × transverse × craniocaudal), with a 12 mm orifice located just above the aortic annulus. It exhibits homogeneous contrast opacification and extends anterolaterally and inferiorly into the interventricular septum, directed toward the right ventricle.

Figure 5 - Intraoperative image showing the opening of the aneurysmal sac prior to closure with a bovine pericardial patch.

Outcomes

Among seven surgically treated sinus of Valsalva aneurysm patients (six ruptured, one unruptured), there were no operative or in-hospital deaths. All underwent successful patch-based repair, with mean cardiopulmonary bypass and aortic cross-clamp times of 165.9 + 36.1 and 126.9 ± 37.9 minutes, respectively. ICU stay averaged 2 days, and hospitalization ranged from 7 to 11 days. No significant complications occurred; minor issues included transient atrial fibrillation (Case 5) and reversible renal dysfunction (Case 4). Only Case 3 required reoperation for patch-related AR; one patient had a small residual shunt (Case 4), which remained stable. At a mean follow-up of 35 months, all patients were NYHA Class I–II with well-functioning prosthetic valves (n=4) and no thromboembolic or anticoagulation-related complications. The valve replacement rate (57%) exceeded the typical series (<20%) [2,5], reflecting complex pathology in Cases 3, 5, and 7. Universal patch closure—using Dacron, PTFE, or pericardium—was employed, consistent with literature favouring it over direct suturing [2,9]; no re-ruptures or late failures occurred. Transaortic repair sufficed in most, while dual approaches were reserved for complex anatomy (e.g., SVC rupture in Case 1, VSD in Case 4). These outcomes highlight the efficacy of individualized, patch-based strategies even in anatomically challenging RSVA cases.

Discussion and Literature Review

To contextualize our findings, we reviewed published series and key reports on SVA over the past three decades. Table 2 summarizes selected studies highlighting case volume, rupture patterns, surgical approach, associated defects, valve interventions, and outcomes.

Literature Review Summary Table

Table 2: Summary of major published series on SVA (ruptured and unruptured)

Although uncommon, sinus of Valsalva aneurysm (SVA) presents a diverse clinical and surgical landscape. Our single-centre experience with seven patients (six ruptured, one unruptured) reflects both the classical and atypical spectrum of SVA, echoing patterns in large published series while adding unique features such as a left coronary sinus (LCS) rupture into the superior vena cava (SVC) and an unruptured case requiring multivalve intervention.

In line with global data, the right coronary sinus (RCS) was the most frequent site of origin (86% in our series), with rupture predominantly into the right ventricle (83%)—figures consistent with large series reporting 71–90% RCS involvement and 58–83% right ventricular rupture [1–6,8–11,13–15]. Ventricular septal defects (VSDs) were seen in 57% of our patients, aligning with reported rates of 29–66% [1–11,13–15]. Similarly, aortic regurgitation (AR) of moderate or greater severity necessitating valve surgery occurred in 57%, exceeding the 5–35% range in literature, possibly due to aggressive management of cusp distortion or pre-existing valvular disease [1–11,13–15].

Patch-based surgical repair was used universally in our cohort, consistent with modern consensus favouring patch over direct sutures due to their lower recurrence rates [2,4,6,12]. Multiple studies, including Sarıkaya et al., confirm the superiority of patch repair, with recurrence rates near zero compared to up to 50% with suturing alone [9]. Depending on case complexity and availability, the materials used included Dacron, PTFE, and bovine pericardium.

Our valve replacement rate (57%) was higher than in most series (5–20%) [2,5,8], driven by structural pathology (Case 5), patch-related AR (Case 3), and multivalvular involvement (Case 7). While repair remains an option in selected AR cases, we favoured valve replacement in young patients to ensure long-term durability and optimal ventricular unloading.

Operative outcomes were excellent, with zero in-hospital Mortality and no significant complications. This mirrors 0–4% mortality rates in most large studies [1–11,13–15]. At long-term follow-up (1 to 6 years), all patients remained in NYHA Class I–II with well-functioning repairs or prosthetic valves and no thromboembolic complications.

Transcatheter closure, while increasingly attempted, remains limited to select anatomies. In our series, two patients presented after failed device deployment—one with embolization and one with residual shunt—highlighting well-documented limitations such as device migration and incomplete closure in complex lesions [6,7,10]. Current evidence and our experience reinforce the role of surgical correction as the gold standard in RSVA with associated lesions or unfavourable anatomy.

The heterogeneity in SVA presentation underscores the importance of individualized surgical planning. Our case of LCS rupture into the SVC—an exceedingly rare phenomenon—illustrates the value of preoperative imaging in delineating complex anatomies and guiding surgical approaches. Similarly, including an unruptured aneurysm requiring multivalve replacement emphasizes that even non-ruptured SVAs can pose a significant hemodynamic burden.

Surgical repair of ruptured and unruptured sinus of Valsalva aneurysm (SVA) offers excellent early and mid-term outcomes when performed in experienced centres. In our series, patch repair yielded 100% early survival with no significant complications, reaffirming it as the preferred approach. The high prevalence of associated lesions—including ventricular septal defect (VSD) and significant aortic regurgitation (AR)—emphasizes the need for comprehensive intraoperative assessment and tailored surgical strategy.

Our AVR rate of 57%, although higher than in many prior series, reflects a conservative and definitive management philosophy aimed at minimizing residual pathology. Notably, all valve replacements were performed in appropriately selected cases for severe structural valve disease, acute worsening of AR post-repair, or preoperative cusp distortion. This highlights the importance of individualized valve decision-making in RSVA surgery, especially in young patients where long-term anticoagulation implications must be weighed carefully.

Moreover, atypical rupture sites (such as into the SVC) and cases with prior failed device closure reinforce that early surgical referral should remain the gold standard, particularly when anatomy is complex or when transcatheter techniques fail or are contraindicated. Our findings suggest that even in such scenarios, excellent outcomes can be achieved with meticulous surgical planning and execution.

In conclusion, successful outcomes in SVA management depend on early diagnosis, precise imaging, individualized operative planning, and adherence to principles of durable repair. Multicentre registries and longer follow-up data are needed to better guide management strategies, particularly for unruptured aneurysms and the evolving role of transcatheter interventions.

1. Vural M, Sener E, Ozatik MA, Taşdemir O. Surgery for ruptured sinus of Valsalva aneurysm: 53 cases. Eur J Cardiothorac Surg. 2001;20(1):71-4.
2. Takach TJ, Reul GJ, Duncan JM, et al. Sinus of Valsalva aneurysm or fistula: management and outcome. Ann Thorac Surg. 1999;68(5):1573-7.
3. Wang ZJ, Zou CW, Li DC, et al. Surgical repair of sinus of Valsalva aneurysm in Asian patients. Ann Thorac Surg. 2007;83(2):552-6.
4. Yan F, Wang Y, Zhu Y, et al. Surgical repair of sinus of Valsalva aneurysm: 100 cases. Asian Cardiovasc Thorac Ann. 2008;16(4):345-9.
5. Choudhary SK, Bhan A, Sharma R, et al. Aneurysms of the sinus of Valsalva: surgical experience in 104 patients. Ann Thorac Surg. 1997;64(2):432-7.
6. Cullen S, Somerville J, Redington A. Transcatheter closure of a ruptured aneurysm of the sinus of Valsalva. Br Heart J. 1994;71(5):479-80.
7. Kerkar PG, Loya YS, Punamiya RM, et al. Transcatheter device closure of ruptured sinus of Valsalva. Catheter Cardiovasc Interv. 2006;67(4):653-7.
8. Dong C, Wu QY, Tang Y, et al. Surgical treatment of sinus of Valsalva aneurysm. Chin Med J (Engl). 2002;115(7):1035-7.
9. Sarikaya S, Adademir T, Elibol A, et al. Surgical repair of ruptured sinus of Valsalva aneurysm: outcomes and long-term follow-up. Tex Heart Inst J. 2013;40(1):34-7.
10. Perloff JK. The clinical recognition of congenital heart disease. 6th ed. Philadelphia: Saunders Elsevier; 2012. p. 35–8.
11. Chu SH, Hung CR, How SS, et al. Ruptured aneurysms of the sinus of Valsalva in oriental patients. J Thorac Cardiovasc Surg. 1990;99(2):288-98.
12. Weinreich M, Yu PJ, Trost B. Sinus of Valsalva aneurysms: review of the literature and an update on management. Clin Cardiol. 2015;38(3):185-9.
13. Murashita T, Kubota S, Yamauchi S, et al. Surgical repair of ruptured sinus of Valsalva aneurysm: 35-year single-institution experience. Ann Thorac Surg. 2002;73(5):1460-5.
14. Zhao SH, Yan Y, Song YH, et al. Surgical treatment of sinus of Valsalva aneurysm. J Card Surg. 2003;18(2):173-6.
15. Lin CY, Lin YT, Wang MJ, et al. Surgical results of ruptured sinus of Valsalva aneurysm. Int J Cardiol. 2004;96(2):237-41.
16. Padhy AK, Sistla CV, Gupta A. Left sinus of Valsalva aneurysm rupturing into superior vena cava. Asian Cardiovasc Thorac Ann. 2019;27(8):677–80. doi:10.1177/0218492319878019
17. Au WK, Chiu SW, Mok CK, Lee WT, Cheung D, He GW. Repair of ruptured sinus of Valsalva aneurysm: determinants of long-term survival. Ann Thorac Surg. 1998; 66:1604–10.
18. Azakie A, David TE, Peniston CM, Rao V, Williams WG. Ruptured sinus of Valsalva aneurysm: early recurrence and fate of the aortic valve. Ann Thorac Surg. 2000;70(6):1466–70. doi:10.1016/S0003-4975(00)01015-7