Triple-Vessel Coronary Artery Disease Associated with Familial Hyperhomocysteinemia

Suvir Singh; Bishav Mohan

doi:10.4103/rcm.rcm_34_20

CASE REPORT

Year : 2020 | Volume : 9 | Issue : 4 | Page : 107-110

Triple-Vessel Coronary Artery Disease Associated with Familial Hyperhomocysteinemia

Suvir Singh¹, Bishav Mohan²
¹ Department of Clinical Hematology, Dayanand Medical College, Ludhiana, Punjab, India
² Department of Cardiology, Dayanand Medical College, Ludhiana, Punjab, India

Date of Submission	24-Aug-2020
Date of Decision	19-Sep-2020
Date of Acceptance	06-Oct-2020
Date of Web Publication	24-Dec-2020

Correspondence Address:
Dr. Suvir Singh
Department of Clinical Hematology, Dayanand Medical College, Ludhiana, Punjab
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/rcm.rcm_34_20

Abstract

Homocysteine is a sulfhydryl containing amino acid implicated in the pathogenesis of cardiovascular disease in multiple epidemiologic studies. However, elevated homocysteine in isolation is not known to lead to severe coronary artery disease requiring emergency intervention. We report a previously asymptomatic 55-year-old gentleman who presented with an acute myocardial infarction with bradycardia and was found to have triple-vessel coronary artery disease on angiography. After stabilization, he underwent a coronary artery bypass grafting in view of the severity of disease. A thorough evaluation revealed the absence of all traditional risk factors except elevated serum homocysteine. The evaluation of family members also revealed elevated homocysteine levels in both his sons and wife. Mutation testing of the methylenetetrahydrofolate reductase (MTHFR) gene showed homozygous Q429A mutation in the patient and heterozygous A222V and Q429A mutation in both his sons. The patient was discharged successfully and is well after 9 months of follow-up. Homocysteine has been implicated in the pathogenesis of cardiovascular disease in synergy with other traditional risk factors. This is a rare presentation of familial hyperhomocysteinemia presenting with severe coronary artery disease and elevated homocysteine levels in all family members. Elevated homocysteine levels in isolation may lead to significant cardiovascular disease and should be checked if no other risk factors are present. It may be useful to screen the patient and family members for underlying MTHFR mutations. In the absence of prospective evidence, there appears to be little harm in providing multivitamins to attempt to reduce homocysteine levels.

Keywords: Cardiac, heart, homocysteine, ischemia, risk

How to cite this article:
Singh S, Mohan B. Triple-Vessel Coronary Artery Disease Associated with Familial Hyperhomocysteinemia. Res Cardiovasc Med 2020;9:107-10

How to cite this URL:
Singh S, Mohan B. Triple-Vessel Coronary Artery Disease Associated with Familial Hyperhomocysteinemia. Res Cardiovasc Med [serial online] 2020 [cited 2021 Apr 22];9:107-10. Available from: https://www.rcvmonline.com/text.asp?2020/9/4/107/304784

Introduction

Homocysteine is a sulfhydryl containing amino acid formed during the synthesis of methionine and cysteine, first derived in 1932.^[1] It plays a critical role in the methylation cycle and is required for endogenous synthesis of cysteine and methionine.^[2] Since its initial discovery, homocysteine has evolved from an unknown entity to a potentially modifiable risk factor for vascular disease, especially when serum levels are elevated beyond 15 umol/L.^[3],[4] Homocysteine by itself appears unlikely to cause severe cardiovascular disease, and evidence indicates that it works in concert with other risk factors to facilitate pathogenesis.^[4] We report a patient with triple-vessel coronary artery disease requiring emergency coronary artery bypass grafting (CABG), who had elevated homocysteine as the only risk factor, also noted in his family members.

Case Report

Mr. G, a 55-year-old gentleman, previously well and not on any medications presented with sudden onset of chest pain, for which he was evaluated elsewhere. He was found to have nonspecific ST-T wave changes in the anterolateral leads, following which a coronary angiography (CAG) was performed. It revealed triple-vessel disease, and the patient was referred to us for further management. Initial examination was remarkable for bradycardia but otherwise stable vital signs. Initial electrocardiogram showed sinus bradycardia (heart rate = 40/min) with T inversion and ST depression in I, aVL. He was taken up for an emergency CAG, which confirmed triple-vessel disease, with 90% occlusion in distal left anterior descending (LAD) and 100% occlusion in the OM1 branch of the left circumflex. In addition, the distal right coronary artery (RCA) showed 90% obstruction with a long segment plaque. The angiographic findings are summarized in [Figure 1],[Figure 2],[Figure 3].

Figure 1: LAO cranial view +61 +25 view showing occlusion in the left anterior descending (white arrow) and OM (black arrow) branches

Click here to view

Figure 2: RAO caudal view +28 +27 showing occlusion in the left anterior descending (black arrow) and diagonal (white arrow) branches of the left coronary artery

Click here to view

Figure 3: LAO cranial +40 +37 showing extensive left anterior descending disease with vessel calcification

Click here to view

Further evaluation revealed a normal hemogram, renal, and hepatic profiles. As there was no history of smoking or previous cardiovascular symptoms, other risk factors were looked at. There was no evidence of left ventricular (LV) hypertrophy on echocardiography, and testing for glycated hemoglobin, antinuclear antibodies, and antiphospholipid antibodies were negative. Fasting lipid profile was as follows: total cholesterol 156 mg/dl, triglycerides 122 mg/dl, low-density lipoprotein cholesterol 108 mg/dl, and high-density lipoprotein cholesterol 40 mg/dl. High sensitivity C-reactive protein and lipoprotein A were not checked. The patient's 10-year cardiovascular disease risk as calculated by the atherosclerotic cardiovascular score was borderline, at 5.3%. As no risk factors were present, serum homocysteine levels were checked and found to be significantly elevated (149 umol/L, normal 4–15 umol/L). There was no family history of premature cardiac disease, and there was no history of consanguineous marriage in the family

He was taken up for revascularization by CABG, which revealed heavily calcified plaques in RCA, posterior descending artery, and posterior LV branches, rendering them nongraftable. Composite graft using the left internal mammary artery to LAD and the right internal mammary artery to OM1 was performed. He was stabilized postoperatively and discharged uneventfully on the 6^th hospital day. Further evaluation for elevated homocysteine levels showed the presence of homozygous Q429A (1298A > C) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. Homocysteine levels were also checked in both his sons and wife, and all three had significant elevation of the same. Mutation analysis revealed compound heterozygous mutations for A222V (667c > T) and Q429A (1298A > C) in both the sons. The results of testing are summarized in [Table 1]. The patient's wife was not available for genetic testing. All three were started on supplementation with pyridoxine, thiamine, and cyanocobalamin. The patient continues to do well 9 months after follow-up and has no significant symptoms.

Table 1: Details of methylenetetrahydrofolate reductase polymorphisms detected in family members

Click here to view

Discussion

Our patient demonstrates a number of intriguing phenomena. First, he had triple-vessel coronary artery disease, presenting for the first time as acute myocardial infarction and hyperhomocysteinemia as the only risk factor. Second, his wife and both sons were noted to have significantly elevated homocysteine levels, and MTHFR mutations were detected in both the sons. This led to a query on the role of homocysteine in causing cardiovascular disease and the potential risk to family members. We provide a concise summary of evidence for the same.

The association of homocysteine with vascular disease was first noted in 1969, when infants with homocystinuria were noted to have characteristic changes in arterial walls. Inspite of having variable genetic defects, elevated serum homocysteine and vascular changes were the only common findings, leading to a possible association between the two.^[5] It is now known that two major categories of genetic defects lead to congenitally elevated serum homocysteine levels. The first group consists of single-nucleotide polymorphisms in the 5,10 MTHFR leading to methylation cycle defects.^[6] The second group consists of polymorphisms in the MTHFR gene leading to lower enzyme efficacy.^[2]

Elevated serum homocysteine is the end product of both these classes of genetic defects, and multiple mechanisms have been described to link this to the development of vascular disease. Homocysteine is seen to increase systemic inflammation, leading to accelerated atherosclerosis and instability of preexisting plaques.^[7] This is mediated by increased expression of pro-inflammatory cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha.^[8] Local pro-inflammatory action on the medulla oblongata leading to increased sympathetic tone and elevated blood pressure is also postulated to play a role.^[9] Homocysteine also increases the extent of vascular calcification and is uniformly isolated locally from atheroma biopsies.^[10] More recently, alteration of S-adenosylmethionine: S-adenosylhomocysteine ratio at the cellular level due to elevated homocysteine has been indirectly seen to lead to global DNA hypomethylation, which is progressively being recognized as an epigenetic modifier of cardiovascular diseases.^[11] Ischemic heart disease from other causes is mediated by the development of atherosclerotic plaques and arterial wall changes.^[12] Homocysteine-mediated vascular disease demonstrates a greater role of vascular thrombosis with lesser contribution of arterial wall pathology.^[13]

The importance of homocysteine as a risk factor independent of other “traditional” risk factors has been under scrutiny. The cardiovascular system (CVS) risk for any individual is a composite of traditional risk factors such as diabetes, hypertension, hypercholesterolemia, smoking, dietary factors, and a component of unknown risk factors. It is estimated that worldwide, approximately 2/3^rd of the risk of cardiovascular disease is attributable to traditional risk factors, and the remaining 1/3^rd is unexplained.^[4] Up to 20% of patients with cardiovascular disease do not have any identifiable risk factors.^[14] This fact may attain greater importance in the Indian setting, where over 35% of CVS deaths are seen to occur in the age group of 30–65 years, where the prevalence of typical risk factors may be low.^[15] Homocysteine may be one of the factors accounting for this residual unexplained risk.

An association between elevated serum homocysteine and vascular disease has been noted in multiple epidemiological studies.^[16],[17] The risk attributable to homocysteine as an independent cardiovascular risk factor has continued to vary and is a matter of debate.^[4] In a large meta-analysis of over 6000 events, lower levels of serum homocysteine were seen to correlate with a mildly lower risk of cardiovascular events, indicating a modest role on the pathogenesis of heart disease.^[18] Homocysteine levels independently correlate with coronary artery calcification scores in patients with an intermediate Framingham risk score for CVS disease.^[19] Data indicating an epidemiological association between homocysteine elevation and CVS risk are summarized in [Table 2].

Table 2: Summary of meta-analyses evaluating an association between serum homocysteine levels and cardiovascular mortality

Click here to view

As our patient's family members had elevated serum homocysteine, the question of risk posed to each person and the role of homocysteine reduction is paramount. The role of homocysteine reduction in primary prevention of cardiovascular disease has been questioned in multiple randomized trials. However, none of these studies have shown a significant effect on acute cardiac events or mortality.^[20],[21] A Cochrane review analyzing 71,422 subjects found little to no evidence for the reduction of cardiovascular events and mortality by targeting homocysteine levels.^[22] Thus, the current evidence is insufficient to recommend homocysteine reduction in an uncontrolled manner to reduce CVS outcomes. It may have a role in a focused population with elevated homocysteine levels that do not respond to supplementation, or in those with an especially high risk due to other risk factors.^[23] We initiated our patient and his family on oral thiamine, pyridoxine, folate, and B12 supplementation, which has been shown to reduce homocysteine levels. In the absence of evidence to the contrary, there appears to be little harm in providing oral water-soluble vitamins till further evidence is available. The effect of homocysteine is likely additive to other risk factors, which must be judiciously controlled in this setting.

To summarize, epidemiological studies have shown an association between elevated homocysteine levels and a higher cardiovascular risk. However, no studies have demonstrated a reduction in subsequent mortality with reduction of homocysteine levels, a question that is still open to a randomized trial. In any patient presenting without traditional cardiovascular risk factors, estimation of serum homocysteine levels may be beneficial to identify the patient and screen family members.

In a patient who presents with unexplained arterial or venous thromboembolic events, evaluation for homocysteine may be worthwhile to detect patients who have a potentially modifiable risk factor. In addition, screening the family members with serum homocysteine may be justified, as the treatment for elevated homocysteine levels is simple and effective.^[26]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Lecture HK. Investigations into the Properties of Substances at Low Temperatures, Which Have Led, amongst Other Things, to the Preparation of Liquid Helium, Nobelprize. org. Nobel Media AB; 2014.
2.	Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet 1999;354:407-13.
3.	Wierzbicki AS. Homocysteine and cardiovascular disease: A review of the evidence. Diab Vasc Dis Res 2007;4:143-50.
4.	Faeh D, Chiolero A, Paccaud F. Homocysteine as a risk factor for cardiovascular disease: Should we (still) worry about? Swiss Med Wkly 2006;136:745-56.
5.	McCully KS. Vascular pathology of homocysteinemia: Implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969;56:111-28.
6.	Zheng Y, Ramsamooj S, Li Q, Johnson JL, Yaron TM, Sharra K, et al. Regulation of folate and methionine metabolism by multisite phosphorylation of human methylenetetrahydrofolate reductase. Sci Rep 2019;9:4190.
7.	Cao L, Guo Y, Zhu Z. Study of the inflammatory mechanisms in hyperhomocysteinemia on large-artery atherosclerosis based on hypersensitive c-reactive protein-a study from Southern China. J Stroke Cerebrovasc Dis 2019;28:1816-23.
8.	Djuric D, Jakovljevic V, Zivkovic V, Srejovic I. Homocysteine and homocysteine-related compounds: An overview of the roles in the pathology of the cardiovascular and nervous systems. Can J Physiol Pharmacol 2018;96:991-1003.
9.	Zhong MF, Zhao YH, Xu H, Tan X, Wang YK, Wang WZ. The cardiovascular effect of systemic homocysteine is associated with oxidative stress in the rostral ventrolateral medulla. Neural Plast 2017;2017: Article ID 3256325.
10.	van Campenhout A, Moran CS, Parr A, Clancy P, Rush C, Jakubowski H, et al. Role of homocysteine in aortic calcification and osteogenic cell differentiation. Atherosclerosis 2009;202:557-66.
11.	Loscalzo J, Handy DE. Epigenetic modifications: Basic mechanisms and role in cardiovascular disease (2013 Grover Conference series). Pulm Circ 2014;4:169-74.
12.	Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol 2010;30:1282-92.
13.	Carson NA, Dent CE, Field CM, Gaull GE. Homocystinuria: Clinical and pathological review of ten cases. J Pediatr 1965;66:565-83.
14.	Smith SC Jr. Current and future directions of cardiovascular risk prediction. Am J Cardiol 2006;97:28A-32A.
15.	Fuster V, Voûte J. MDGs: Chronic diseases are not on the agenda. Lancet 2005;366:1512-4.
16.	Kaplan ED. Association between homocyst(e) ine levels and risk of vascular events. Drugs Today (Barc) 2003;39:175-92.
17.	Baszczuk A, Kopczyński Z. Hyperhomocysteinemia in patients with cardiovascular disease. Postepy Hig Med Dosw (Online) 2014;68:579-89.
18.	Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: A meta-analysis. JAMA 2002;288:2015-22.
19.	Kullo IJ, Li G, Bielak LF, Bailey KR, Sheedy PF 2^nd, Peyser PA, et al. Association of plasma homocysteine with coronary artery calcification in different categories of coronary heart disease risk. Mayo Clin Proc 2006;81:177-82.
20.	Ebbing M, Bønaa KH, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen K, et al. Combined analyses and extended follow-up of two randomized controlled homocysteine-lowering B-vitamin trials. J Intern Med 2010;268:367-82.
21.	Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage JM, Bowman L, Clarke RJ, Wallendszus K, Bulbulia R, et al. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: A randomized trial. JAMA 2010;303:2486-94.
22.	Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev 2017;8:CD006612.
23.	Chrysant SG, Chrysant GS. The current status of homocysteine as a risk factor for cardiovascular disease: A mini review. Expert Rev Cardiovasc Ther 2018;16:559-65.
24.	Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: Evidence on causality from a meta-analysis. BMJ 2002;325(7374):1202. doi:10.1136/bmj.325.7374.1202.
25.	Clarke R, Bennett DA, Parish S, Verhoef P, Dötsch-Klerk M, Lathrop M, et al. MTHFR Studies Collaborative Group. Homocysteine and coronary heart disease: Meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS Med 2012;9:e1001177.
26.	Rui Fan et al should be: Fan R, Zhang A, Zhong F. Association between Homocysteine Levels and All-cause Mortality: A Dose-Response Meta-Analysis of Prospective Studies. Sci Rep 2017;7:4769.