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Year : 2019  |  Volume : 6  |  Issue : 1  |  Page : 13-18

Comorbid conditions responsible for the higher complications and poorer outcome in cardiac and vascular surgery: Time to reconsider hyperhomocysteinemia and its repercussions

Department of CTVS, Dhiraj Hospital, Vadodara, Gujarat, India

Date of Web Publication8-Mar-2019

Correspondence Address:
Dr. Arun Kumar Haridas
Department of CTVS, Dhiraj Hospital, Vadodara, Gujarat
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijves.ijves_40_18

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Background: Plasma homocysteine is a perceived risk factor for the cardiovascular diseases. Many studies confirmed its remarkably high level with severity of the disease. There are no studies to correlate plasma homocysteine level and outcome of surgery in patients suffering from cardiovascular diseases. Objective: The purpose of our clinical study is to analyze the correlation of plasma Homocysteine levels in patients undergoing coronary artery bypass grafting (CABG) and various peripheral vascular surgeries regarding various patient variables such as age, sex, and also the severity of disease and outcome of surgery. Materials and Methods: The plasma homocysteine levels of 200 patients undergoing CABG and various vascular surgeries, between January 2016 and January 2018 were analyzed. This was a prospective study, data about patient variables obtained from questionnaires handed out to the patients during the preoperative period. All peripheral arterial diseases patients were symptomatic and belong to Rutherford stage 3, 4, 5, and 6. The severity of disease was evaluated based on coronary angiogram (CAG), who was undergoing CABG and computed tomography (CT) angiograms for patients presenting with peripheral vascular disease (PVD) and peroperative findings. A total of 178 CAG and 100 CT peripheral angiograms assessed. Homocysteine levels were determined by CLIA method and levels of >13 mmol/L taken as hyperhomocysteinemia. All patients had surgical vascular intervention in the form of CABG, peripheral vascular bypass, and thromboembolectomy. The results and complications evaluated postoperatively. Result: Higher homocysteine levels associated with a higher number of triple vessel coronary disease and symptomatic PVD. They had greater severity of the disease. It is also associated with poorer target vessels with an increased morbidity and postoperative fatality. Conclusion: Homocysteine level is one of the independent risk factors for severity of CAD. It can have predictive value in CABG, peripheral vascular surgery, and poor postoperative outcome.

Keywords: Angiogram, bypass graft, coronary artery, homocysteine, risk factor

How to cite this article:
Haridas AK, Bhat BS. Comorbid conditions responsible for the higher complications and poorer outcome in cardiac and vascular surgery: Time to reconsider hyperhomocysteinemia and its repercussions. Indian J Vasc Endovasc Surg 2019;6:13-8

How to cite this URL:
Haridas AK, Bhat BS. Comorbid conditions responsible for the higher complications and poorer outcome in cardiac and vascular surgery: Time to reconsider hyperhomocysteinemia and its repercussions. Indian J Vasc Endovasc Surg [serial online] 2019 [cited 2020 Jun 4];6:13-8. Available from:

  Introduction Top

Worldwide, coronary artery disease (CAD) and peripheral arterial diseases (PADs) are the major cause of mortality and morbidity.[1] There are many risk factors that contribute to CAD and PAD, such as dyslipidemia, smoking, hypertension, diabetes, and newer entity on the avenue considered independent risk factor is hyperhomocysteinemia.[2],[3]

Many researchers have acknowledged the hyperhomocysteinemia is responsible for progressive atherosclerotic vascular disease, hypercoagulability of blood, activation of platelets, and clotting factors. Hyperhomocysteinemia evidently convinced that it is associated with premature vascular diseases irrespective of age and cause.[4]

Plasma homocysteine levels are a strong predictor of mortality in patients with CAD and PAD. It is associated with an increased incidence of myocardial infarction, critical limb ischemia, and stroke.[5],[6]

Free plasma homocysteine is responsible for the pathological effects on the organ vasculature. It affects the endothelial function, platelet function, and coagulation system. It induces endothelial dysfunction, enhance the growth of vascular smooth muscles, which contribute to the progression of severity of atherosclerotic pathophysiology and prothrombotic status of vessels made prone for in situ vessel thrombosis.[7],[8] It also increases the platelet aggregation contributing aforementioned facts to enhance criticality of ischemia of organs. There are however few studies which try to test the severity of coronary artery disease (CAD), peripheral vascular disease (PAD), and its outcome after surgery in relation to the hyperhomocysteinemia levels. The aim of our study was to test the correlation of plasma homocysteine levels in patients with cardiovascular diseases, who were undergoing coronary artery bypass grafting (CABG) and various peripheral vascular bypass surgeries in Indian patients.

  Materials and Methods Top


Ours was a prospective single-center study of 200 patients that took place in cardiovascular and thoracic surgery department, from January 2016 to January 2018. All 200 patients underwent CABG and various peripheral vascular operations. For the CABG, left internal mammary artery(LIMA) and reversed great saphenous vein (RSVG) used. The Dacron, PTFE and reversed great saphenous vein (RSVG) grafts used for peripheral vascular bypass surgery based on location of PAD. Patients with kidney disease in any form, vascular embolism <15 days excluded from the study. The study authorized by the Ethics Committee. All patients gave us their informed written consent. Patient's detailed history taken on admission regarding presenting complaints, associated risk factors.


Homocysteine levels of all the patients analyzed in the preoperative period. Homocysteine levels were estimated by CLIA method and levels of >13 mmol/L taken as hyperhomocysteinemia. Hyperhomocysteinemia divided into four groups on the basis of plasma homocysteine level.

The followings are:

  • Normal - <13 mmol/L
  • Mild - 13.1 mmol/L–30 mmol/L
  • Moderate - 30.1 mmol/L–50 mmol/L
  • Severe - above 50.1 mmol/L.

Patient's Coronary angiogram and computed tomography peripheral angiogram was evaluated. Peroperative findings of the coronary vessels, all peripheral vessels condition and character assessed during surgery.

Postoperative recovery was assessed by the vital data, ventilator requirement, the number of intensive care unit (ICU) days, and the need for postoperative inotropic support. Postoperative morbidity and mortality analyzed in detail.

Statistical analysis

The statistical software used for statistical analysis is SPSS 20 (IBM corp, SPSS Statistics, Armonk, Newyork). P < 0.05 was considered statistically significant.

  Results Top

In the study, 200 patients were included. Of these, 100 patients underwent CABG, other 100 patients underwent various peripheral vascular surgeries, and three underwent concomitant CABG and aortobifemoral grafting (ABFG).

The age group of patients varied from 25 to 83 years. The homocysteine levels varied with age. The highest homocysteine levels were found in the age group of 51–70 years [Figure 1].
Figure 1: Plasma homocysteine as per age groups

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In our study, there was a greater preponderance of hyperhomocysteinemia in men compared to women in each age group, but it was not significant (P = 0.377) [Figure 2].
Figure 2: Plasma homocysteine and gender

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Smoking was associated with increased homocysteine levels in the study with statistically significant (P = 0.007) [Figure 3].
Figure 3: Plasma homocysteine in smokers

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One hundred and twenty patients were hypertensive and 122 patients were diabetic. The association of hyperhomocysteinemia with hypertension and diabetes mellitus was not statistically significant [Figure 4].
Figure 4: Plasma homocysteine level and hypertension

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Among the patients with CAD, who underwent CABG, two patients had single vessel disease with left main coronary artery (LMCA) involvement. Fifteen patients had double vessel disease of which two had LMCA disease. Eighty-three patients had triple vessel disease with 28 having LMCA disease [Figure 5].
Figure 5: Plasma homocysteine and coronary artery disease

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One hundred patients from CAD group and three patients from PAD group who had CAD underwent CABG. Left internal mammary artery (LIMA) and reversed great saphenous vein (RSVG) grafts used for CABG. Twenty-five (12.5%) had aortoiliac occlusive disease underwent ABFG using Dacron bifurcating graft. Three (1.5%) cases had femorofemoral jump grafting using ringed PTFE graft for iliac artery occlusive disease. Thirty (15%) patients underwent femoropopliteal bypass using PTFE, Dacron and reversed great saphenous vein (RSVG) grafts for femoro-popliteal occlusive diseases. Forty-two (21%) cases undergone successful thromboembolectomy for thromboembolism using Fogarty artery embolectomy and Fogarty adherent clot removal catheter [Table 1].
Table 1: Diagnosis and surgery done

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Out of the 103 CABG patients, 68 patients had grafting of LIMA to the left anterior descending artery.

Eighteen patients needed right coronary artery endarterectomy on the table during CABG. All of these patients had hyperhomocysteinemia [Figure 6].
Figure 6: Plasma homocysteine and coronary artery endarterectomy

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In our study, we found a significant association of hyperhomocysteinemia with increased requirement of inotropic support and increased postoperative ICU stay [Figure 7].
Figure 7: Plasma homocysteine and coronary artery bypass grafting outcome

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The pattern of PAD in accordance with Rutherford classification is as follows: in Stage III 51 cases (51%), Stage IV 42 cases (42%), Stage V five cases (5%), and Stage VI two cases (2%) [Table 2].
Table 2: Rutherford classification for peripheral arterial disease

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Three patients with peripheral vascular disease were found to have concurrent CAD with left main CAD and required concomitant CABG with peripheral arterial bypass on a priority basis. All three patients had hyperhomocysteinemia [Figure 8].
Figure 8: Incidence of concomitant coronary artery bypass grafting and peripheral vascular disease surgery

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Hyperhomocysteinemia was associated with significant preoperative gangrene in patients of PAD requiring intervention in the form of amputation during the vascular procedure (P = 0.001) [Figure 9].
Figure 9: Plasma homocysteine level and incidence of preoperative gangrene

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In the PAD subgroup, 58 of the 100 required bypass grafting and the rest were managed with thromboembolectomy using Fogarty arterial embolectomy catheter and Fogarty adherent clot removal catheter of the affected vessels [Figure 10].
Figure 10: Plasma homocysteine and peripheral arterial disease surgery

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In the vascular subgroup of patients, postoperative gangrene occurred in five patients, and all five had hyperhomocysteinemia. Underwent amputation of affected part in the same hospital stay in <15 days [Figure 11].
Figure 11: Incidence of postoperative gangrene

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The outcome of procedure in PAD was significantly associated with the homocysteine levels of the patient. Patients had a better recovery when with lower homocysteine levels. Whereas, those patients with hyperhomocysteinemia had poorer outcomes [Figure 12].
Figure 12: Plasma homocysteine and peripheral arterial disease surgery outcome

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  Discussion Top

Homocysteine is an amino acid, generated by catabolism of methionine. Homocysteine dependent on various vitamins as the cofactor for its degradation, any deficiency of such vitamin enhances the level of homocysteine in the individual. It is found to be increased with elderly people, renal dysfunction patients, and smokers. Hyperhomocysteinemia induces endothelial dysfunction with its endothelial proliferation, enhance endothelial prothrombotic status attracting platelet aggregation, and promoting coagulation cascade so contributing to progressive atherosclerosis and in situ thrombosis.[9]

Hyperhomocysteinemia is modifiable, independent known risk factor for CAD and PAD. It increases the incidence of multiple myocardial infarction and peripheral limb ischemia.[9],[10] Uniformly, it involves all vasculature of the body. It consistently involves coronary artery, peripheral vasculature, and cerebrovascular vessel.[11] It is also found to be associated evidently with an increased incidence of venous thrombosis.[12]

In 1969, McCully made the correlation between high homocysteine and vascular disease. It is proved hyperhomocysteinemia induces atherosclerosis.[13] In 1976, Wilcken and Wilcken showed that hyperhomocysteinemia associated with CAD, PAD, and proved that it is linked with the heightened proportion of morbidities and mortality.[14]

Although some studies conducted in India did not show increased homocysteine levels among patients with CAD. It may not be reliable as they studied in a minuscule group of patients.[15],[16] Our study showed profound association of hyperhomocysteinemia with increased severity of CAD and PAD.

Our study indicates that the prevalence of hyperhomocysteinemia in preoperative patients is astoundingly high involving, 85% of our study population. This is coherent with the findings of other western studies. Despite that, independent comorbid condition like hyperhomocysteinemia and its detrimental effects is disregarded while treating the patients presenting with cardiovascular disease.

Our study revealed increased homocysteine levels, seemingly associated with smoking which is the most common practice in rural society. This is consistent with the finding in other studies.[17],[18] Smoking itself directly responsible for hyperhomocysteinemia or not remained to seen with further concrete researches.

In this study, we found increased severity of coronary artery and peripheral vascular artery diseases. These findings were substantiated with peroperative findings. The patient had multiple vessel involvement, numerous short distance skip lesion, and overall diffuse narrowing of distal vessels. There was a raised incidence of endarterectomy in both coronary as well as peripheral vasculature. Peroperatively, such patients required unusually more number of grafts than predicted. Typically in peripheral vascular surgery needed not only merely multiple bypasses but also multiple endarterectomy and patch plasty for better distal runoff. The same proved in other studies.[19]

In our study, we found a considerable association of hyperhomocysteinemia with an increased demand of inotropic support, intra-aortic balloon pump support, increased ICU stay for post-CABG patients. Post peripheral vascular surgery associated with an increased proportion of re-thrombosis of graft needing reexploration and embolectomy. There was also a high rate of amputation in patients, who had a high level of homocysteine. Dictum is higher the homocysteine; more is the associated morbidities and mortality.

Recently completed large randomized controlled trials, supplementation of folic acid, vitamin B6, and vitamin B12 has been revealed to decrease homocysteine levels over a period.[20] However, that treating patients with hyperhomocysteinemia with supplementation of vitamin B has failed to decrease cardiovascular morbidity and mortality, perhaps as disease is already set in and immutable.[21]

The investigations that have been promulgated so far regarding the effects of raised Homocysteine levels, on vessels and their atherothrombotic predisposition has demonstrated with increased CAD, PAD in hyperhomocysteinemia. This is legitimate in our research as well.

Homocysteine levels can foresee the severity of cardiovascular disease and poor outcome of the treatment whatsoever way. It has been established that curtailing the considerably elevated circulating homocysteine, greatly reduces cardiovascular risk.[22] Supplementation of folic acid has been shown to decrease homocysteine levels.[23] However, further researches are recommended to confirm the role of various nutritional supplementations and other forms intervention if any for decreasing the homocysteine levels. It is also time to study long-term benefits of such treatment for either interruption of progression or revoking the changes it has contributed to organ vasculature.

  Conclusion Top

Hyperhomocysteinemia is an independent risk factor taken seriously such as diabetes. Homocysteine level can predict morbidity and mortality risk in patients who are undergoing cardiovascular surgery.

The identification of hyperhomocysteinemia in such patients may allow the surgeon to modify and plan his procedure, for the better outcome.

It requires aggressive management with anticoagulants and nutritional supplementation in view of the increased risk of thromboembolic events due to underlying diffuse vasculature disease and prothrombotic endothelium. It is an innate character of patients with hyperhomocysteinemia.

Routine supplementation of folic acid and other vitamin has to be evaluated further in such cases to look out for long-term benefits in reversing the underlying pathology.

There is a demand for further studies regarding precautions and protective strategies to be undertaken in patients with hyperhomocysteinemia suffering from cardiovascular disease and undergoing vascular surgical intervention.


Our study is a single center study with a limited number of patients. The conclusions of our study need to be validated with further trials. In patients undergoing emergency cases, homocysteine evaluation avoided.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol 1996;27:517-27.  Back to cited text no. 1
Setti KK, Mantri RR. Homocysteine -emerging evidences as an independent risk factor for CAD. Cardiol Today 1999;3:122-9.  Back to cited text no. 2
Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE,et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997;337:230-6.  Back to cited text no. 3
Bhargava S, Srivastava LM. Homocysteine-Marker of the millenium. A review of its evolution and clinical implication. J Med Sci 2001;4:104-16.  Back to cited text no. 4
Gheye S, Lakshmi AV, Krishna TP, Krishnaswamy K. Fibrinogen and homocysteine levels in coronary artery disease. Indian Heart J 1999;51:499-502.  Back to cited text no. 5
Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D,et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992;268:877-81.  Back to cited text no. 6
Sahu R, Murthy A. Hyperhomocysteinemia and in situ renal artery thrombosis: A diagnostic challenge and a novel treatment strategy. Indian J Med Specialities 2015;6:111-5.  Back to cited text no. 7
Tan YM, Chia KH. Acute thrombosis associated with hyperhomocysteinemia. Eur J Vasc Endovasc Surg 2002;24:279-80.  Back to cited text no. 8
Castro R, Rivera I, Blom HJ, Jakobs C, Tavares de Almeida I. Homocysteine metabolism, hyperhomocysteinaemia and vascular disease: An overview. J Inherit Metab Dis 2006;29:3-20.  Back to cited text no. 9
Abraham R, John MJ, Calton R, Dhanoa J. Raised serum homocysteine levels in patients of coronary artery disease and the effect of Vitamin B12 and folate on its concentration. Indian J Clin Biochem 2006;21:95-100.  Back to cited text no. 10
Gravina-Taddei CF, Batlouni M, Sarteschi C, Baltar VT, Salvarini NA, Bertolami MC,et al. Hyperhomocysteinemia as a risk factor for coronary atherosclerotic diseases in the elderly. Arq Bras Cardiol 2005;85:166-73.  Back to cited text no. 11
Berwanger CS, Jeremy JY, Stansby G. Homocysteine and vascular disease. Br J Surg 1995;82:726-31.  Back to cited text no. 12
McCully KS. Vascular pathology of homocysteinemia: Implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969;56:111-28.  Back to cited text no. 13
Wilcken DE, Wilcken B. The pathogenesis of coronary artery disease. A possible role for methionine metabolism. J Clin Invest 1976;57:1079-82.  Back to cited text no. 14
Deepa R, Velmurugan K, Saravanan G, Karkuzhali K, Dwarakanath V, Mohan V,et al. Absence of association between serum homocysteine levels and coronary artery disease in South Indian males. Indian Heart J 2001;53:44-7.  Back to cited text no. 15
Chacko KA. Plasma homocysteine levels in patients with coronary heart disease. Indian Heart J 1998;50:295-9.  Back to cited text no. 16
Haj Mouhamed D, Ezzaher A, Neffati F, Douki W, Najjar MF. Effect of cigarette smoking on plasma homocysteine concentrations. Clin Chem Lab Med 2011;49:479-83.  Back to cited text no. 17
O'Callaghan P, Meleady R, Fitzgerald T, Graham I; European COMAC Group. Smoking and plasma homocysteine. Eur Heart J 2002;23:1580-6.  Back to cited text no. 18
Ranucci M, Ballotta A, Frigiola A, Boncilli A, Brozzi S, Costa E,et al. Pre-operative homocysteine levels and morbidity and mortality following cardiac surgery. Eur Heart J 2009;30:995-1004.  Back to cited text no. 19
Miller ER 3rd. Dose-dependent effects of folic acid on blood concentrations of homocysteine: A meta-analysis of the randomized trials. Am J Clin Nutr 2005;82:806-12.  Back to cited text no. 20
Bønaa KH, Njølstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T,et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006;354:1578-88.  Back to cited text no. 21
Brattström L, Wilcken DE. Homocysteine and cardiovascular disease: Cause or effect? Am J Clin Nutr 2000;72:315-23.  Back to cited text no. 22
Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE,et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med 2010;170:1622-31.  Back to cited text no. 23


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12]

  [Table 1], [Table 2]


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