We thank the reader for the comments and also for the lengthly discussion of various possible risk factors (the latter issues were beyond the scope of our manuscript). However, we must correct a key misinterpretation by the reader. As pointed out in our article, the findings were applicable in all geographic regions and all healthcare systems (for example in Europe this includes the UK, France, Belgium, Germany, Spain). Thus the findings cannot be accounted for by the influence of refunding in private healthcare systems. Keith A A Fox

Sir, The risk of death in acute coronary syndrome(ACS) before admission to hospital is upto 20%. However, death rates, after admission to the hospital have decreased greatly; upto 7% patients die before discharge and risk of death continues to be high for six months after the ACS(1). Apart from risk of mortality, a similar risk remains for reinfarction after admission to the hospital in the next one year after discharge.Fox and colleagues(2), have very nicely concluded that proceeding to percutaneous coronary intervention(PCI) relates to referral practice and angiographic findings, rather than the patients risk status. However, this conclusion may be biased and possible only in private hospitals where experts earnings depend on the number of interventions done by them and may not be correct for hospitals where cardiac surgeons and interventional cardiologists are paid fixed salary.

We agree that systematic and accurate risk stratification may allow high-risk ACS patients to be chosen for suitable revascularization procedure.However, it seems that identification of high risk patients for cardiac events, is challenging, because our knowledge regarding high risk patients remains unpredictable.Risk stratification based simply on biomarkers and electrocardiographic changes is limited within diagnosis of angiographic coronary artery obstruction and ST-segment elevation or non- ST elevation myocardial infarction.It is well known to intervention experts that high risk patients are elderly, have left ventricular failure and have documented ST segment changes in the electrocardiogram and it is these patients where coronary angiography is a must, to rule out the role of revascularization.Unfortunately,our experts work better than they can think about various risk factors responsible for recurrent cardiac events.The exact pathogenesis of coronary thrombosis remains controversial, hence present methods for stratification of risk are also very crude.Most experts agree that unstability of the atherosclerotic plaque is most important determinant of ACS, however risk factors for increased vulnerability of plaque are not considered during treatment of ACS.Apart from the specific risk predictors, drug therapy with statins, ACE-inhibitors, betablockers, aspirin, clopidogral and glycoprotein receptor blockers are important in modification of risk in patients with ACS.It is well known that thrombosis in a plaque depends upon the quality and stability of atheroma rather than on extent of coronary artery obstruction. Therefore, any risk factors that can influence the quality and composition of plaque should be stratified for risk prediction in ACS patients.

Adverse lifestyle and diet such as increased consumption of proinflammatory foods; refined starches and sugar, trans fatty acids, w-6 fatty acids and saturated fat and trans fatty acids(TFA) and deficiency of w-3 fatty acids and monounsaturated fatty acids, may increase free fatty acids,oxidative stress and proinflammatory cytokines, causing endothelial dysfunction(3,5). Endothelial dysfunction may be responsible for the unstability of atheroma.Therefore eating proinflammatory foods could be an important predictor and cause of bad prognosis in ACS, because these patients have a preexisting proinflammatory milieu in association with atherothrombosis or an unstable plaque(3-5).There is no consideration of clocks,rhythms and triggers as predictors of circadian rhythms of ACS in the morning between 6.00 to 12.00 hours(6).

ACS appear to be due to thrombosis in the vulnerable plaque, and may be associated with activation of neurohormones and proinflammatory cytokines, resulting into neuroendocrine dysfunction, which may be associated with recurrent cardiac events. There may be oxidative stress, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, increased levels of catecholamines, free fatty acids and cortisol, which further enhance the risk of atherothrombosis in an unstable plaque(7-10). There is increased superoxide ion generation in leukocytes and mononuclear cells,on glucose ingestion in normal subjects, with enhanced activity of nuclear factor-fÛB (NF-fÛB), a transcriptional factor regulating the activity of at least 125 genes, most of which are pro inflammatory(5,7- 10). Refined carbohydrates also causes an increase in two other pro- inflammatory transcription factor,activating protein-1(AP-1) and Egr-1, the first regulating the transcription of matrix metallo-proteinases and the second modulating the transcription of tissue factor and plasminogen activator inhibitor-1.These adverse factors related to diet may be independent predictors of ACS.There is activation of NF-fÛB associated with the generation of reactive oxygen species (ROS) by mononuclear cells, on consumption of a mixed meal(5,6).Superoxide anion appear to be an activator of at least two major pro-inflammatory transcription factor , NF-fÛB and AP-1. Previous findings, demonstrate that after oral or intravenous glucose challenges, in both normal subjects and patients with type 2 diabetes mellitus, there is an increased generation of ROS and raised circulating levels of proinflammatory cytokines, such as TNF-fÑ,IL- 6 and IL-18(4-6). A single high-fat meal produces endothelial activation, as evidenced by increased concentrations of the adhesion molecules VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1), in association with raised plasma concentrations of IL-6 and TNF-fÑ.(5-7). A high-fat meal which may be large, may increase the circulating levels of IL-18, a pro-inflammatory cytokine supposed to be involved in plaque destabilization associated with the simultaneous decrease of circulating adiponectin, an adipocyte-derived protein with insulin sensitizing, anti-inflammatory, and antiatherogenic properties.However, eating a high-fat meal together with vegetable foods rich in natural antioxidants largely prevent the negative effects on endothelial function(5,6).Endothelial dysfunction acutely triggered by the consumption of a high-fat meal rich in saturated fatty acids is reduced by the simultaneous consumption of a vegetable serving including pepper (100g) tomatoes (100g), and carrots (200g).It seems that these foods are slowly digested and absorbed without causing any significant increase in free radical stress and free fatty acids, which is a characteristic of Columbus foods(www.Columbus-concept.com) and therefore such foods may improve the prognosis in ACS(2,5,6).

In one study(5), among 54 patients with ACS, and 85 control subjects, drawn from a similar age and sex of the subjects, increased consumption of TFA (>5g/day) was significantly greater among ACS patients compared to controls(50.0 vs 0.0%,n=27 vs 0).Large meals(>1000 K cal)(50.0 vs 29.4%,n=27 vs 25) and large breakfast(40.7% vs 11.8%,n=22 vs 10), rich in TFA,linoleic acid, saturated fat and refined carbohydrates intakes were also significantly(P<0.02) greater among ACS patients,compared to control subjects.Only 2 out of 54 patients died during the hospitalization period of 4days to 10days and another 2 patients were referred for coronary angiography and possible revascularization.However,only one volunteered for angioplasty with stents for treatment. Serum level of nitrite(a indicator of nitric oxide,NO) was significantly lower in patients with ACS compared to controls(mean+SD:0.36+1.42 vs 0.96+1.48uM,CI difference 0.60,0.34-1.02,P<0.03).The incidence of lipoprotein(a) excess(>30mg/dl) and mean levels of lipoprotein(a)(difference 6.4mg/dl,95% confidence interval 2.8- 10.5,P<0.05) was significantly greater in the ACS group compared to control subjects.Serum levels of vitamins E,C and beta-carotine,coenzyme Q10,magnesium and potassium were significantly lower and insulin,glucose,triglycerides,and lipoprotein(a),TNF-alpha,and IL-6 were significantly higher in ACS compared to controls.There was a significantly greater occurrence of acute ACS events in the second quarter of the day(40.7 vs 18.3,12.9,27.7%,P<0.02)compared to other quarters.

The differences in the nitrite levels in the two groups indicate that low levels of nitrite appears to be a risk factor of ACS. Reduction in antioxidants vitamins may be due to increased oxidative stress which is common in ACS due to enhanced free radical generation which may also influence NO levels and cause endothelial dysfunction. Therefore,it may be proposed that any factor which can block neuroendocrine activation would be protective, whereas other factors that can enhance neurohormonal activity would be the risk factors of ACS or recurrent cardiac events.It seems that in India, proceeding to revascularization depends more upon economic status of the patients than on referral practice or actual indication to the ACS patients.In our centre,we refer patients for coronary angiography,if there are persistent manifestations of ischaemia despite thrombolysis, and or positive treadmill test after 3-4 weeks of ACS.Infact some poor patients prefer medical therapy despite positive treadmill test.

There is increased platelet aggregation and blood pressure variability and decreased heart rate variability in association with higher concentrations of catecholamines,oxidative stress and cytokines between 6.00 to 12.00hours in the morning(5-7).Eating a heavy breakfast rich in proinflammatory foods; TFA,linoleic acid and refined starches and low in w-3 fatty acids may have predisposed the ACS(1,2). Infact these risk factors continue to operate in patients presenting with ACS but are usually ignored by the cardiologists, while taking decision about revascularization.There is evidence that proinflammatory cytokines are known to insult the neurons which worsens in presence of deficiency of w-3 fatty acids,responsible for the survival of neurons.Omega-3 fatty acids can regulate leptin gene expression and the concentrations of anandamides in the brain,which in turn binds to endogenous cannabinoid receptors and regulate food intake and satiety. However, anticytokine therapy via diet in patients with risk factors, in a few dietary trials(9) showed significant benefit in the intervention group compared to control subjects.In the Indian Experiments(4), a diet rich in w-3 fatty acids(1.8 vs 0.5 g/day alpha linolenic acid) showed significant benefit among ACS patients, compared to control groups.It seems that Stratification of diet and lifestyle factors is important in patients of ACS, that are unlikely to modify their diet, before patients are referred for coronary intervention.Opinions of the authors of above study about our comments would be greatly appreciated(2).

Viola Mechirova,MD,Safaric University,Kosice,Slovakia Garima Singh, Halberg Hospital and Research Institute,Civil Lines, Moradabad-10(UP)244001,India,email drkk@dataone.in R B Singh,MD,Halberg Hospital and Research Institute, Moradabad- 10(UP)244001,India Fabien DeMeester,PhD,Columbus Paradigm Institute,Bastogne,Belgium Lekh Juneja,PhD,Taiyo Kagaku,Yokkaichi,Japan Daniel Pella,MD, Faculty of Medicine,Safaric University,Kosice,Slovakia Email, pellad@hotmail.com

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