Spectrum of coronary artery disease in seropositive syphilis patients in the modern era

Mullusoge Mariappa Harsha; Srinidhi Hegde; Ashwini Mahadevaiah; Santhosh Krishnappa; Kanchanahalli Siddegowda Sadananda; Manjunath Cholenahally Nanjappa

doi:10.4103/jcpc.jcpc_35_21

ORIGINAL ARTICLE

Year : 2022 | Volume : 11 | Issue : 1 | Page : 22-26

Spectrum of coronary artery disease in seropositive syphilis patients in the modern era

Mullusoge Mariappa Harsha¹, Srinidhi Hegde¹, Ashwini Mahadevaiah², Santhosh Krishnappa¹, Kanchanahalli Siddegowda Sadananda¹, Manjunath Cholenahally Nanjappa³
¹ Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Science and Research, Mysuru, Karnataka, India
² Department of Microbiology, Sri Jayadeva Institute of Cardiovascular Science and Research, Mysuru, Karnataka, India
³ Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Science and Research, Bengaluru, Karnataka, India

Date of Submission	31-May-2021
Date of Acceptance	29-Dec-2021
Date of Web Publication	21-Apr-2022

Correspondence Address:
MD DM Mullusoge Mariappa Harsha
Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Mysore Branch, K.R.S Road, Mysuru, Karnataka
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jcpc.jcpc_35_21

Abstract

Context: Cardiovascular manifestations of tertiary syphilis include aortitis, aortic aneurysm, aortic regurgitation, and coronary ostial stenosis. There are few reported cases of coronary aneurysms and coronary dissection. However, in the modern era of antibiotics, classic manifestations are rarely seen. We intend to study the spectrum of coronary artery disease in seropositive syphilis patients undergoing cardiac catheterization. Subjects and Methods: Coronary angiogram of 150 patients seropositive for syphilis from March 2019 to April 2020 was reviewed. Seropositive for both Venereal Disease Research Laboratory and Treponema Pallidum Hemagglutination Assay tests were an essential inclusion criterion. Prevalence of left main stenosis, coronary ostial stenosis, aneurysms, dissections, and other features were studied and compared to standard prevalence in the general population undergoing coronary angiogram. Results: Mean age was 56 years and 109 (73%) were male. Thirty-three percent were smokers, 39% were diabetic, 45% hypertensive, and 5% had prior stroke. We noticed left main stenosis in 8%, isolated ostial left main stenosis in 1.3%, spontaneous coronary artery dissection in 0.7%, and coronary aneurysm and ectasia in 4%; a similar prevalence to the general population as compared with earlier trials. Conclusion: In the present study, there was no significant increase in aorto-ostial stenosis, coronary aneurysm, or coronary dissection in seropositive syphilis patients. The classic manifestations of tertiary syphilis are rare in the modern era. All syphilis patients should be treated with proper antibiotics, as a case of giant aneurysm post left main ostial stenting was noticed in an untreated patient.

Keywords: Aorto-ostial stenosis, cardiovascular syphilis, coronary aneurysm, spontaneous coronary artery dissection

How to cite this article:
Harsha MM, Hegde S, Mahadevaiah A, Krishnappa S, Sadananda KS, Nanjappa MC. Spectrum of coronary artery disease in seropositive syphilis patients in the modern era. J Clin Prev Cardiol 2022;11:22-6

How to cite this URL:
Harsha MM, Hegde S, Mahadevaiah A, Krishnappa S, Sadananda KS, Nanjappa MC. Spectrum of coronary artery disease in seropositive syphilis patients in the modern era. J Clin Prev Cardiol [serial online] 2022 [cited 2023 Jun 8];11:22-6. Available from: https://www.jcpconline.org/text.asp?2022/11/1/22/343643

Introduction

Syphilis, caused by the bacterium Treponema pallidum, is associated with significant complications if left untreated. The incidence of syphilis has been increasing ever since 2000 when the lowest rate was noted.^[1] A corresponding increase of patients presenting with cardiovascular manifestations can occur if undiagnosed or left untreated. Cardiovascular syphilis is the manifestation of tertiary syphilis, primarily an arteritis of vasa vasorum, usually occurs between 10 and 30 years after the initial infection in about 10%–15% of untreated patients.^[2],[3] Cardiovascular manifestations include aortitis, aortic root dilation, aneurysm formation, aortic regurgitation, coronary ostial stenosis, and rarely myocarditis.^[4],[5]

Coronary ostial lesions are detected in as many as 26% of patients with syphilitic aortitis.^[6] There are few reported cases of coronary aneurysms and spontaneous dissection secondary to vasculitis in syphilis patients.^[7],[8] Clinical presentation due to coronary involvement can be stable angina, unstable angina, myocardial infarction, or heart failure. There are many reported cases of acute ST-elevation myocardial infarction secondary to coronary ostial involvement.^[9] Cardiac catheterization and intervention for coronary artery disease in such patients pose difficulties because of ostial lesions, bilateral ostial lesions, aneurysms, and spontaneous dissection. Coronary artery bypass surgery also poses technical challenges because of aortitis, aortic dilatation, calcification, fibrosis, and arch vessel involvement. However, there are no large studies of seropositive syphilis patients undergoing coronary angiogram to the best of our knowledge. In the modern era of antibiotics, classic manifestations are rarely seen. We intend to study the spectrum of coronary artery disease in seropositive syphilis patients undergoing cardiac catheterization.

Subjects and Methods

The study was conducted at a tertiary cardiac center in South India. This is a retrospective observational study from March 2019 to April 2020. Among 10198 patients screened, syphilis prevalence was 1.98%, of which 150 patients underwent angiogram; the rest 52 patients were presurgical, heart failure admissions, or did not undergo angiogram for various reasons. Written consent was obtained for participation and publication from all patients in line with COPE guidelines. The institutional ethical committee has approved the study.

Testing for syphilis

Our primary screening method is nontreponemal Venereal Disease Research Laboratory (VDRL) test. Those who test positive for VDRL are confirmed with treponemal Treponema Pallidum Hemagglutination Assay (TPHA). Only patients positive for both VDRL and TPHA tests were included in the study due to concern of false-positive VDRL test.

The authors studied case files of seropositive syphilis patients for the need for admission, concurrent cardiovascular risk factors, echocardiogram, and indication for coronary angiogram. Two independent cardiologists reviewed coronary angiograms of all patients. The presence of ≥50% stenosis in the left main or ≥70% in other vessels was considered significant. Prevalence of aorto-ostial stenosis, left main disease, coronary aneurysms, and dissection were studied and compared with the standard prevalence in patients undergoing angiogram. Aorto-ostial stenosis is defined as significant stenosis up to 3 mm of coronary origin.^[10] Coronary artery aneurysm is localized dilatation of more than 1.5 times the adjacent normal segment. A more diffuse dilatation is considered ectasia.^[11] The presence of ascending aortic calcification was noted.

Statistical analysis

Data were entered into Microsoft Excel (Windows 7; Version 2007), and analyses were done using the Statistical Package for the Social Sciences (SPSS) for Windows software (version 22.0; SPSS Inc., Chicago, IL, USA). Descriptive statistics such as mean and standard deviation for continuous variables, frequencies, and percentages were calculated for categorical variables were determined. Cronbach's alpha coefficient and Cohen's kappa statistic were used to know the intra- and inter-observer variability, respectively, and the values obtained were 0.67 and 0.73, respectively.

Results

We studied a total of 150 consecutive seropositive syphilis patients who underwent coronary angiograms. The mean age of patients is 56 years. One hundred and nine patients were male (73%) and 41 female (27%). Thirty-three percent were smokers, 39% were diabetic, and 45% were hypertensive. Eight patients (5%) had a history of prior stroke. The main indication for coronary angiogram was acute coronary syndrome with STEMI accounting for 47%, NSTEMI 26%, and unstable angina in 7%. Thirteen percent underwent angiogram for stable angina, while 3% for heart failure evaluation. Among the less common indications, four were for presurgical cardiac, one patient presurgical noncardiac, and two with hypertrophic cardiomyopathy. Thirteen patients had undergone prior percutaneous angioplasty and three prior CABG [Table 1].

Table 1: Baseline characteristics

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Twelve patients (8%) had >50% left main luminal stenosis, of which two had isolated left main ostium disease, five with diffuse left main disease, and five involving bifurcation sparing ostium. Three patients had RCA ostial disease, of which one had isolated ostial lesion. None of the three post-CABG patients had aorto-ostial lesions of venous grafts. Coronary aneurysm was seen in three patients, two involving the left main and one in the circumflex artery. A 57-year-old patient who had undergone patient angioplasty for ostial left main disease 4 years back had giant coronary aneurysm. The patient was seropositive for syphilis during the index procedure too. He had been asked to meet venereologist during discharge, which he had not complied. Three patients had coronary ectasia involving each right coronary, left anterior descending, and circumflex artery. The present study did not have any patient with aneurysm or ectasia involving multiple vessels. One patient had spontaneous coronary artery dissection involving the left circumflex artery. About 19% of patients had triple-vessel disease, 25% double-vessel disease, and 34% single-vessel disease. Moderate coronary calcification was seen in 17% and severe in 14%. Four patients had visible ascending aortic calcification [Table 2] and [Figure 1].

Table 2: Coronary manifestations

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Figure 1: (a) Coronary aneurysm, (b) coronary aneurysm postostial left main stenting, (c) ectasia, (d) ostial stenosis, (e) spontaneous coronary artery dissection, (f) dense ascending aorta calcification

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Discussion

Syphilis is an infectious disease occurring in sequential stages, remaining latent for several decades. Tertiary syphilis manifests between 10 and 30 years after the primary infection in 30% of untreated patients. Cardiovascular syphilis is a late complication of untreated syphilis that affects 12.8% of patients after average disease duration of 30 years.^[12] Syphilitic aortitis, typically involving ascending aorta, is the most common manifestation. Syphilitic aortitis leads to aortic insufficiency, aortic aneurysm, and/or coronary ostial stenosis. Cardiovascular syphilis cases are still reported despite effective antibiotic therapy and public health awareness. The most common complication of untreated syphilitic aortitis is aortic regurgitation.^[13] Coronary ostial stenosis occurs in 20% of patients with syphilitic aortic insufficiency. Classic histopathology includes a “tree bark” appearance of the aortic intima, inflammatory infiltrate of the medial, and adventitial vasa vasorum and endarteritis obliterans of the vasa vasorum.^[14]

Syphilis can primarily cause coronary artery disease in the form of ostial stenosis, coronary aneurysms, and coronary dissection.^[6],[7],[8] These lesions are per se difficult to treat, require planning, expertise and is associated with suboptimal immediate and long term results. Associated aortic root dilatation adds to the problem.^[4] However, more often, seropositivity for syphilis is just an incidental finding in atherosclerotic coronary artery disease patients. We planned this study to know the prevalence of such lesions in seropositive syphilis patients undergoing coronary angiograms.

There was significant left main disease in 12 patients and isolated left main ostial stenosis in two patients. The prevalence of triple-vessel disease was 18%, which is similar to that observed by Rastan et al. (20.7%).^[15] Significant left main disease is seen in 2.2% to 17% depending on the clinical scenario.^{[16],[17],[18],[19]} D'Ascenzo et al. in a meta-analysis in the ACS subgroup reported 12% incidence.^[16] In a study by Soleimani et al., significant and minimal LMCA stenosis were found in 3.6% and 6.4% of patients, respectively.^[17] Isolated ostial left main disease is a rare entity, occurs in 0.05%–0.88% of patients undergoing angiogram.^{[18],[19],[20]} Srinivas et al. reported an incidence of 0.18% among 15,553 patients.^[18] In this study, there was no increased prevalence of left main stenosis or aorto-ostial lesions in the syphilis group compared to the general population in earlier studies.

Syphilitic aortitis results in chronic inflammation, ischemic necrosis, and fibrosis of tunica media leading to coronary ostial stenosis. The pathological changes are different from atherosclerosis.^[20] Nakazone et al. reported a case of a young patient with acute myocardial infarction due to severe bilateral coronary ostial stenosis induced by syphilitic aortitis highlighting the rare etiology of coronary artery lesions secondary to tertiary syphilis.^[21] Similar cases of bilateral coronary ostial stenosis with moderate aortic regurgitation were described by Tanaka et al. and Matsuyama et al.^[22],[23]

The prevalence of angiographic coronary calcification was 31% with 17% having moderate calcification and 14% having severe calcification. Mintz et al. had reported angiogram-based moderate and severe coronary calcification in 26% and 12%, respectively, in a cohort of 1155 patients with target lesions.^[24] There were four patients with severe ascending aortic calcification. All had severe calcific coronary lesions, suggesting aortic calcification likely secondary to atherosclerosis. Although linear ascending aorta calcification was initially described characteristic of syphilitic aortitis, it is also noticed with advanced atherosclerosis and aortic valve disease.^[25] Aortic arch calcification is an independent predictor of the severity of coronary artery disease.^[26] Saphenous venous grafting in such patients will be difficult because given aortic inflammation and calcification with increased risk of future graft failure because of medial fibrosis at the proximal anastomotic site. The use of internal mammary arteries may cut the risk, although aortic arch and brachiocephalic trunk involvement can occur.^[27]

The reported incidence of coronary aneurysms varies from 0.2% to up to 5.3%. Wang et al. reported coronary aneurysm prevalence of 0.25% in a patient cohort of 10,120 patients.^[28] Coronary artery surgery study registry investigators reported a higher prevalence of 4.9%.^[29] We noticed coronary aneurysm in three patients and ectasia in three patients, a similar prevalence to earlier studies (4%). One patient with post percutaneous angioplasty to ostial left main disease 4 years back, presenting with effort angina had giant coronary aneurysm. Untreated syphilis with chronic inflammation could have led to the aneurysm, although other causes cannot be ruled out.

Spontaneous coronary artery dissection was present in one patient, a similar incidence in earlier studies. Clare et al. reported SCAD in 0.78% among a cohort of 26598 patients with acute myocardial infarction.^[30] There is not much literature on the association of syphilis with coronary dissection. Rafiq et al. reported a case of coronary artery dissection that could be secondary to the vasculitic manifestation of tertiary syphilis.^[7] There was no increased prevalence of SCAD in syphilis patients in our study.

This study is unique as there are no data in this subset of patients except for case reports. To the best of our knowledge, there are no reported large studies to date. In a random seropositive syphilis patient undergoing angiogram, the present study throws light on the occurrence and frequency of coronary manifestations of tertiary syphilis. The prevalence of these manifestations is so low that syphilis patients should not be denied of emergency coronary procedures. The study has a few limitations. This is a retrospective study. Visual inspection was used to estimate coronary stenosis and not quantitative coronary angiography. We did not classify patients according to stages of syphilis; although with a mean age of 56 years, most patients would be in latent syphilis. As our primary screening method was VDRL followed by confirmation with TPHA, we would not have included cured patients with remote syphilis infection treated with appropriate antibiotics for respective stages. All patients were treated with three doses of long-acting benzathine penicillin G 2.4 million units (1.2 million units administered in each buttock intramuscularly) at weekly intervals.

Conclusion

There is no significant increase in aorto-ostial stenosis, coronary aneurysm, or coronary dissection in seropositive syphilis patients. The classic manifestations of tertiary syphilis are rare in the modern era, likely limited to few case reports. All syphilis patients should be treated with proper antibiotics, as a case of giant coronary aneurysm, post left main ostial stenting occurred in an untreated patient. With the growing prevalence of syphilis, vigilance is essential.

Acknowledgment

We are grateful to Dr. Prashanth Bettappa for his help in statistical analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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