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J Am Coll Cardiol, 2007; 49:1370-1371, doi:10.1016/j.jacc.2007.01.014
(Published online 8 March 2007). © 2007 by the American College of Cardiology Foundation |
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* Director, Coronary Care Unit, Shifa International Hospital, H-8/4, Islamabad, Pakistan (Email: samraakhtar{at}hotmail.com).
There is consistency in the mean homocysteine level in patients with coronary artery disease (CAD) from Pakistan and India of about 19 µmol/l (3–8). This finding is significant because the South Asian population has the highest known rate of CAD, which is widespread, early onset, and is aggressive (9). They have higher propensity for clinical events compared with other populations even after adjusting for all known risk factors and the degree of atherosclerosis (10).
The concept of homocysteine being a proximate risk factor with short incubation period and its strong interaction with conventional risk factors provides a biological plausibility that, in South Asians, homocysteine owing to its prothrombotic effects and interaction with conventional risk factors may increase the propensity of this population to develop coronary atherothrombotic disease (11). According to one estimate, in Pakistan nearly 100,000 individuals suffered from acute myocardial infraction in calendar year 2002 (12). These observations are undermined especially in meta-analyses as a majority of the studies are done in the population with lower mean homocysteine values. The sample size in the meta-analysis of patients with homocysteine >15 µmol/l and especially in the range of 19 µmol/l is not powered to give statistically significant conclusions. This observation is obvious in the high-impact trials like HOPE (Heart Outcome Prevention Evaluation)-2 and NORVIT (Norwegian Vitamin Trial), where the mean homocysteine values of patients were 12.2 µmol/l and 13.0 µmol/l, respectively (13,14). In view of the mandated fortification of food products in the U.S., it was predicted beforehand that the statistical power of the ongoing trials would be marked by power shortage (15).
Ironically, the trend-setting study "Folate Therapy and In-Stent Restenosis After Coronary Stenting" (16) in its conclusion never mentioned the trend toward the beneficial effect of folate replacement in patients with homocysteine levels >15 µmol/l, and the study became a landmark trial showing increase risk of in-stent restenosis with folate therapy, which was documented in patients with homocysteine levels <15 µmol/l.
The scenario is further biased by the fact that after folic acid fortification in the United States, a population-wide reduction in blood homocysteine concentration has been seen; according to one estimate, the proportion of patients with homocysteine >15 µmol/l decreased from 41% to 28%. This mean decrease in homocysteine levels in this population has nicely translated in terms of trend toward mortality benefit in cardiovascular disease and definite improvement in stroke-related mortality (17,18). These facts are well appreciated by Kaul et al. in defining the therapeutic range of high-risk individuals in the recommendations for screening and treatment of elevated homocysteine levels.
How do developing countries, which form a major chunk of global burden (2) of cardiovascular disease, reconcile with the invalidation of homocysteine hypothesis for atherothrombosis? In the long run, its repercussions could be in the form of the 10/90 gap, which refers to the global situation where only 10% of billions of dollars is devoted to health research, which accounts for 90% of total health burden (19).
Finally, this state-of-the-art study is food for thought in context to the philosophy to achieve maximum diversity nicely highlighted by Anthony DeMaria in the Journal’s Editor’s Page, "Diversity in JACC" (20).
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