Primary prevention and risk factor reduction in coronary heart disease mortality among working aged men and women in eastern Finland over 40 years: population based observational study
BMJ 2016; 352 doi: https://doi.org/10.1136/bmj.i721 (Published 01 March 2016) Cite this as: BMJ 2016;352:i721
All rapid responses
Dear Editor,
I appreciate the excellent long-term work on risk factors for coronary heart disease carried out by Jousilahti et al.1 I suggest that along with the risk factors considered by them, investigators and clinicians should include deficiency in the mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) as an another important risk factor. This deficiency is caused by a common dominant mutant allele of ALDH2 whose odds ratio for myocardial infarction appears to be similar to or even greater than that of tobacco smoking.2
ALDH2 is a well-known enzyme of alcohol metabolism that oxidatively converts cytotoxic acetaldehyde into acetic acid. 30~40% of the entire East Asian population and 8% of the world’s population - thus approximately 560 million individuals - have this inherited ALDH2 deficiency.3 This DNA polymorphism leads to 50 ~ 90% loss of ALDH2 activity.4 However its low frequency among Western people may be responsible for its widespread neglect in Western medical textbooks, and for the fact that even Asian physicians are largely unfamiliar with it.
Recently mitochondrial ALDH2 has emerged as a key cardioprotective enzyme involved in endogenous survival signaling in the heart.5 Cardiac ischemia and reperfusion promote oxidative stress, leading to the accumulation of reactive aldehydes such as acetaldehyde and 4-hydroxy-2-nonenal (4-HNE) that cause cardiac damage via mitochondria dependent apoptosis pathway.4 5 Moreover 4-HNE has been implicated in various levels of atherosclerosis development, including nitric oxide dependent endothelial dysfunction, oxidized LDL associated platelet aggregation, matrix metalloproteinase production in vascular smooth muscle cells, and upregulated cytokines during chronic inflammation.6 In detoxifying these endogenous cytotoxic aldehydes, ALDH2 plays a central role. Good examples of its association with ischemic heart disease are the experiments by Chen et al and Stachowicz et al.5 7 They demonstrated that ALDH2 activity is strongly correlated with infarct size, lower activity leading to larger infarcts, and that ALDH2 activation is linked to inhibition of atherogenesis in apoE knockout mice. Thus, there has been a large volume of research on the clinical implications of these findings.
Individuals with ALDH2 deficiency can be screened with 90% sensitivity and 88% specificity by a simple questionnaire.8 The questionnaire consists of two questions: (A) Do you have a tendency to develop facial flushing immediately after drinking a glass (about 180 ml) of regular beer? (B) Did you have a tendency to develop facial flushing immediately after drinking a glass of beer in the first one or two years after you started drinking? If an individual answers yes to question A or B, he or she is considered to be ALDH2 deficient.
Accordingly, individuals with inactive ALDH2 are at risk of coronary artery disease (CAD) even if they do not have any of the established CAD risk factors. Moreover if an individual with ALDH2 deficiency has one or more classical CAD risk factors, they should receive intensive risk management. Since the number of people with East Asian ethnicity is increasing in Western society,4 even Western physicians need to check for ALDH2 deficiency when they see patients, particularly those of East Asian origin.
References
1. Jousilahti P, Laatikainen T, Peltonen M, et al. Primary prevention and risk factor reduction in coronary heart disease mortality among working aged men and women in eastern Finland over 40 years: population based observational study. BMJ 2016;352:i721.
2. Jo SA, Kim EK, Park MH, et al. A Glu487Lys polymorphism in the gene for mitochondrial aldehyde dehydrogenase 2 is associated with myocardial infarction in elderly Korean men. Clin Chim Acta 2007;382:43-47.
3. Chen CH, Ferreira JC, Gross ER, Mochly-Rosen D. Targeting aldehyde dehydrogenase 2: new therapeutic opportunities. Physiol Rev 2014;94:1-34.
4. Gross ER, Zambelli VO, Small BA, et al. A personalized medicine approach for Asian Americans with the aldehyde dehydrogenase 2*2 variant. Annu Rev Pharmacol Toxicol 2015;55:107-27.
5. Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D. Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science 2008;321:1493–95.
6. Mali VR, Palaniyandi SS. Regulation and therapeutic strategies of 4-hydroxy-2-nonenal metabolism in heart disease. Free Radic Res 2014;48:251-63.
7. Stachowicz A, Olszanecki R, Suski M. Mitochondrial aldehyde dehydrogenase activation by Alda-1 inhibits atherosclerosis and attenuates hepatic steatosis in apolipoprotein E-knockout mice. J Am Heart Assoc 2014;3:e001329.
8. Brooks PJ, Enoch M-A, Goldman D, Li T-K, Yokoyama A. The alcohol flushing response: An unrecognized risk factor for esophageal cancer from alcohol consumption. PLoS Medicine 2009;6:e50:0258–63.
Competing interests: No competing interests
Reconfirm to Follow Guidelines to Prevent Cardiovascular Diseases
Jousilahti P, et al estimated how much changes in the main risk factors of cardiovascular disease (smoking prevalence, serum cholesterol, and systolic blood pressure) could explain the reduction in coronary heart disease mortality observed among working aged men and women in eastern Finland.1 They included 34 525 men and women aged 30-59 years who participated in the national FINRISK studies between 1972 and 2012. They observed that during the 40 year study period, levels of the three major cardiovascular risk factors decreased except for a small increase in serum cholesterol levels between 2007 and 2012. From years 1969-1972 to 2012, coronary heart disease mortality decreased by 82% (from 643 to 118 deaths per 100 000 people) and 84% (114 to 17) among men and women aged 35-64 years, respectively. During the first 10 years of the study, changes in these three target risk factors contributed to nearly all of the observed mortality reduction. Since the mid-1980s, the observed reduction in mortality has been larger than predicted. In the last 10 years of the study, about two thirds (69% in men and 66% in women) of the reduction could be explained by changes in the three main risk factors, and the remaining third by other factors.
This study points risk factor reduction at the population level is an effective way of reducing coronary heart disease mortality and secondary prevention among high risk individuals and treatment of acute events of coronary heart disease could confer additional benefit. Smoking and hypertension are the most common risk factor for cardiovascular disease (CVD). Accordingly, to stop smoking and to control blood pressure (BP) optimally are very important to prevent CVD. In this regard, a meta-analysis of individual data for one million adults in 61 prospective studies reported that throughout middle and old age, usual BP is strongly and directly related to vascular (and overall) mortality, without any evidence of a threshold down to at least 115/75 mm Hg.2 This suggested the lower the systolic blood pressure the lower the risk of CVD. However, recent clinical trials showed controversial results regarding the optimal systolic BP targets. Some favored the lower the better3-6 and others did not7,8. Physicians are now in chaos regarding this important issue.9-11 Brunstrom M, et al evaluated the effect of antihypertensive treatment on mortality and cardiovascular morbidity in people with diabetes mellitus, at different BP levels and observed that antihypertensive treatment reduces the risk of mortality and cardiovascular morbidity in people with diabetes mellitus and a systolic BP more than 140 mm Hg. If systolic BP is less than 140 mm Hg, however, further treatment is associated with an increased risk of cardiovascular death, with no observed benefit.8 Furthermore, physicians should keep in mind rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive treatment group than in the standard-treatment group.5 Furthermore, controlling BP to too lower level is hazardous in elderly patients. Therefore, recent European and American guidelines recommend treatment thresholds below 140 mm Hg in patients with hypertension12,13 and below 150 mm Hg in elderly (age> 70 years old) patients with hypertension13.
On the other hand, hypercholesterolemia and hypertension are both associated with endothelial dysfunction and insulin resistance and their coexistence is associated with an increased incidence of cardiovascular events. Hypercholesterolemia and hypertension have a synergistic deleterious effect on endothelial function, oxidative stress, inflammation, and etc.14,15 Various strategies to reduce residual cardiovascular risk in hypertensive patients included treating BP to lower target goals and using different classes of anti-hypertensive medications, however still considerable residual risk remained. In contrast, controlling hypercholesterolemia in hypertensive patients by statins is very effective in reducing residual cardiovascular risk by 35% to 40%.16 Also, cross-talk between hypercholesterolemia and rennin angiotensin system (RAS) exists at multiple steps of insulin resistance and endothelial dysfunction. In this regard, combined therapy with statins and RAS blockers demonstrate additive/synergistic effects on endothelial dysfunction and insulin resistance in addition to lowering cholesterol levels and blood pressure when compared with either monotherapy in patients.17-20 This is mediated by both distinct and interrelated mechanisms. Therefore, combined therapy with statins and RAS blockers may be important in developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome, or obesity to prevent vascular risk. Nonetheless, a current pretty low incidence taking statins in hypertensive patients is very disappointing.
The other is that patients with CVD or high risk should take several medications with high cost on the long-term period. However, low adherence is the big problem. In this regard, use of a combination strategy for BP, cholesterol, and platelet control vs usual care resulted in significantly improved medication adherence at 15 months and statistically significant but small improvements in BP and cholesterol. There were no significant differences in serious adverse events or cardiovascular events between the groups. Evidence existed of larger benefits in patients with lower adherence at baseline.21
How should we do to reduce other remaining factors? A study investigated to determine the comparative effectiveness of exercise versus drug interventions on mortality outcomes. Although limited in quantity, existing randomised trial evidence on exercise interventions suggests that exercise and many drug interventions are often potentially similar in terms of their mortality benefits in the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes.22 This study points the importance of therapeutic life style changes compared with drugs intervention. All physicians should think about this message in time of many drugs being prescribed while elderly population is increasing fast and life expectancy is longer.23
Funding: None, Disclosures: None
REFERENCES
1. Jousilahti P, Laatikainen T, Peltonen M, et al. Primary prevention and risk factor reduction in coronary heart disease mortality among working aged men and women in eastern Finland over 40 years: population based observational study. BMJ 2016;352 :i721.
2. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to
vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective
studies. Lancet 2002;360:1903-13.
3. Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet 2016;387:435-43.
4. Emdin CA, Anderson SG, Callender T, et al. Usual blood pressure, peripheral arterial disease, and vascular risk: cohort study of 4.2 million adults. BMJ 2015;351:h4865.
5. The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16.
6. Mant J, McManus RJ, Roalfe A, et al. Different systolic blood pressure targets for people with history of stroke or transient ischaemic attack: PAST-BP (Prevention After Stroke-Blood Pressure) randomised controlled trial. BMJ 2016;352:i708.
7. Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; 362: 1575-85.
8. Brunström M, Carlberg B. Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and meta-analyses. BMJ 2016;352:i717.
9. Koh KK. To control blood pressure is important, but not enough to prevent vascular risk BMJ 2015, Published on 16 December 2015, ttp://www.bmj.com/content/351/bmj.h4865/rr-0
10. Koh KK. Redefining blood pressure targets against SPRINT in patients with diabetes? BMJ 2016, Published on 1 March 2016, http://www.bmj.com/content/352/bmj.i717/rr-0
11. Koh KK. Redefining systolic blood pressure targets for people with history of stroke or transient ischaemic attack? BMJ 2016, Published on 2 March 2016, http://www.bmj.com/content/352/bmj.i708/rr
12. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC
guidelines for the management of arterial hypertension: the Task Force for the management
of arterial hypertension of the European Society of Hypertension (ESH) and of the
European Society of Cardiology (ESC). J Hypertens 2013;31:1281-357.
13. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507-20.
14. Koh KK. Quon MJ. Targeting converging therapeutic pathways to overcome hypertension. Int J Cardiol 2009;132:297-9.
15. Oh PC, Sakuma I, Hayashi T, Koh KK. Angiotensin converting enzyme inhibitors remain the first treatment of choice. Korean J Intern Med 2016;31:237-41.
16. Egan BM, Li J, Qanungo S, Wolfman TE. Blood pressure and cholesterol control in hypertensive hypercholesterolemic patients: National health and nutrition examination surveys 1988-2010. Circulation 2013;128:29-41.
17. Koh KK, Quon MJ, Han SH, et al. Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterolemic, hypertensive patients. Circulation 2004;110:3687-92.
18. Koh KK, Quon MJ, Han SH, et al. Vascular and metabolic effects of combined therapy with ramipril and simvastatin in patients with type 2 diabetes. Hypertension 2005;45:1088-93.
19. Lim S, Sakuma I, Quon MJ, Koh KK. Potentially important considerations in choosing specific statin treatments to reduce overall morbidity and mortality. Int J Cardiol 2013;167: 1696-1702.
20. Koh KK, Lim S, Choi H, et al. Combination pravastatin and valsartan treatment has additive beneficial effects to simultaneously improve both metabolic and cardiovascular phenotypes beyond that of monotherapy with either drug in patients with primary hypercholesterolemia. Diabetes 2013;62:3547-552.
21. Thom S, Poulter N, Field J, et al; UMPIRE Collaborative Group. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. JAMA 2013;310:918-29.
22. Naci H, Ioannidis JPA. Comparative effectiveness of exercise and drug
interventions on mortality outcomes: metaepidemiological study. BMJ 2013;347:f5577
23. Koh KK. To take or not to take drugs? That is the question. BMJ 2013, Published 30 December 2013, http://www.bmj.com/content/347/bmj.f5577/rr/679697
Competing interests: No competing interests
Re: Primary prevention and risk factor reduction in coronary heart disease mortality among working aged men and women in eastern Finland over 40 years: population based observational study
there are factors that could contribute to the risk of familial heart attack, such as inherited predisposition to high blood, pressure and influence of a common lifestyle among family members, for this reason is really important the knowledge of personal history not only prior coronary disease, but also other aliments increase the risk factors of this condition. Smoking is the main factor of cardiovascular risk in men and women, therefore it is necesary to star with campaigns against smoking. physical inactivity and adesity plays a very important role in the lives people of people sendentary lifestyle is the cause of health problems.
Competing interests: No competing interests