Valtimotaudin synty, riskit ja lääkitys

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Tänään (9.2.2012) olen mukana paneelikeskustelussa valtimotaudista. Tilaisuus järjestetään 4. tiedepäivien yhteydessä Tampereen yliopistolla. Raportoin mahdollisuuksien mukaan paikan päältä joko terveysblogissani tai Facebookissa.

Valtimotaudin synty, riskit ja lääkitys

Osallistun 9.2.2012 paneelikeskusteluun ”Pathogenesis and risk factors of atherosclerosis with

special emphasis on cholesterol-lowering drugs” (Valtimotaudin synty, riskit ja lääkitys) Tampereen yliopiston lääketieteen laitoksella. Paneelia johtaa professori Ilkka Pörsti ja muina panelisteina esiintyvät professori Matti Uusitupa, emeritus professori Pentti Tuohimaa ja kardiologi Erkki Ilveskoski.

Tässä lyhyesti oma käsitykseni valtimotaudin synnystä, riskitekijöistä ja vielä lopuksi mielipiteeni kolesterolia alentavien lääkkeiden tarpeellisuudesta taudin ennaltaehkäisyssä ja hoidossa.

1. Suomen Sydänliiton ja Käypä hoitosuositus -työryhmän puolustama näkemys valtimotaudin syntymekanismista on minun mielestäni yksipuolinen ja harhaanjohtava. Terveyspropagandistinen näkemys rasvaisen ruoan ja kolesterolin merkityksestä taudin synnyssä ei vastaa nykytieteen käsitystä asiasta. Kun Sydänliitto pitää kynsin hampain kiinni yksipuolisesta käsityksestään, se tekee haittaa kokonaisvaltaisemman käsityksen leviämisestä tietoisuuteemme. Koululääketieteen mukaan kolesteroliteoria on yksi vankimmin toteennäytetyistä lääketieteen alueista, ja tuntuu lähes kohtuuttomalta kritisoida sitä. Kuitenkin minä olen valmis kritisoimaan sitä kuten tulette kuulemaan.
2. Minun mielestäni valtimotauti on ensisijaisesti tulehdussairaus. Tulehdustila johtuu mm. epäterveellisestä ravinnosta, jota syömme (prosessoitu ruoka, transrasvat, sokeri), tupakoinnista ja stressistä. Valtimon seinämien tulehdustila voidaan mitata verikokeella (ns. herkkä CRP). Valtimotaudin syntyyn voi myös vaikuttaa korkea verenpaine kuten emeritus professorit Pentti Tuohimaa ja Matti Järvilehto ovat tieteellisissä keskusteluissaan tuoneet esille. Ateroskleroosin ensi vaiheen ehkäisyssä verenpaineen hoito vaikuttaisi loogisemmalta ratkaisulta kuin kolesterolin alentaminen.
3. Mielenkiintoista on pohtia valtimotautia omega-6-/omega-3-rasvahappojen tasapainon kannalta. En ole kovinkaan vakuuttunut siitä, että mm. professori Uusituvan suosima ajatus siitä, että tyydyttyneet rasvahapot vaihtuessaan monityydyttymättömiin rasvahappoihin, toisivat pysyviä terveyshyötyjä. Tässä vaihtokaupassa ei nimittäin oteta huomioon omega-6-/omega-3-rasvahappojen suhteet. Ramsdenin uusimmassa meta-analyysissa omega-6 ja omega-3-rasvahappolähteet eroteltiin asianmukaisesti toisistaan. Tämän meta-analyysin mukaan omega-6-rasvahapoista ei ollut mitään hyötyä ja mahdollisesti niistä oli jopa haittaa sydäntautien tai kuolleisuuden näkökulmasta. Silti virallinen linja tyrkyttää omega-6-rasvahappoja. Pyydän tälle asialle kunnon selityksen Uusituvalta.
   
   Ramsden CE, Hibbeln JR, Majchrzak-Hong SF. All PUFAs are not created equal: absence of CHD benefit specific to linoleic acid in randomized controlled trials and prospective observational cohorts. World Rev Nutr Diet. 2011;102:30-43. Epub 2011 Aug 5. (Dietary advice to specifically increase n–6 LA has not been based on data that specifically evaluates dietary LA. We have shown here that the prospective observational cohorts put forth as evidence for CHD benefits of n–6 LA have limited ability to disentangle respective intakes and effects of n–6 LA and n–3 ALA using FFQ data. A pooled analysis of four RCT datasets provides the most appropriate data to evaluate the specific CHD effects of increasing LA in place of saturated and trans fatty acids. This analysis found no benefit, and a relatively consistent signal toward harm from selectively increasing LA. We conclude that evidence from RCTs and prospective observational cohorts, the top two tiers of evidence-based medicine, does not support current population-wide advice to maintain or increase consumption of the n–6 PUFA LA.)
   Ramsden CE, Hibbeln JR, Majchrzak SF, Davis JM. n-6 fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a meta-analysis of randomised controlled trials. Br J Nutr. 2010 Dec;104(11):1586-600. (Risk of non-fatal MI+CHD death was significantly higher in n-6 specific PUFA diets compared to mixed n-3/n-6 PUFA diets (P = 0.02). RCT that substituted n-6 PUFA for TFA and SFA without simultaneously increasing n-3 PUFA produced an increase in risk of death that approached statistical significance (RR 1.16; 95 % CI 0.95, 1.42). Advice to specifically increase n-6 PUFA intake, based on mixed n-3/n-6 RCT data, is unlikely to provide the intended benefits, and may actually increase the risks of CHD and death.)
   
   Ramsden on tärkeällä asialla, sillä ihan äskettäin ilmestyi tutkimus, jossa näiden omega-6-/omega-3-rasvahappojen vaikutusta kuolleisuuteen tutkittiin hemodialyysipotilailla. Ravinnon suuri omega-6/omega-3- suhde lisäsi tulehdusta ja kuolleisuutta myös hemodialyysipotilailla.
   
   Noori N and others. Dietary omega-3 fatty acid, ratio of omega-6 to omega-3 intake, inflammation, and survival in long-term hemodialysis patients. Am J Kidney Dis. 2011 Aug;58(2):248-56. Epub 2011 Jun 12. (Higher dietary omega-6 to omega-3 ratio appears to be associated with both worsening inflammation over time and a trend toward higher death risk in hemodialysis patients. Additional studies including interventional trials are needed to examine the association of dietary fatty acids with clinical outcomes in these patients.)
4. Erityiset valkosolut (makrofagit) pyrkivät poistamaan valtimotulehdusta syömällä hanakasti tulehduspesäkkeitä, rasvaa ja kolesterolia. Ahminnan tuloksena makrofagit muuttuvat vaahtosoluiksi ja tulehduksen edelleen edistyessä valtimotauti etenee.
5. Valtimotaudin etenemisessä on keskeisessä roolissa ns. pienikokoinen hapettunut LDL-kolesteroli (syntyy silloin kun syömme epäterveellistä ruokaa), joka tarttuu tulehduskohtaan valtimoissa aiheuttaen ajan mittaan kalkin, kolesterolin ja rasvan kertymistä.
6. Rasvainen ruoka ja kolesteroli on vain yksi riskitekijä monien kymmenien (satojen?) muiden valtimotaudin riskitekijöiden joukossa. Liian yksipuolisesti keskittymällä kolesteroli- ja rasvahypoteesiin ja tukeutumalla voimakkaasti statiineihin, olemme tukeneet kokonaisvaltaista terveyskäsitystä tarpeettomasti rajoittavaa terveydenhoitoa. Kolesteroli on vain yksi riskitekijä muiden joukossa. Ottamalla ennakkoluulottomasti huomioon tulehduksen merkittävän roolin valtimotaudin synnyssä voimme luoda toimivan hoitomallin valtimotaudin ennaltaehkäisyssä (primaaripreventio) ja sen hoidossa (sekundaaripreventio).
7. Valtimotaudin primaaripreventiossa on keskeisessä roolissa liikunta, stressin hallinta ja ennen kaikkea tulehdusta ehkäisevä ns. anti-inflammatorinen ruoka (tuore kala, marjat, hedelmät, pähkinät ja siemenet).
8. Statiinien rooli primaaripreventiossa on hyvin vähäinen. Statiineja ennaltaehkäisevässä mielessä nautittaessa, moni potilas syö aivan turhaan näitä kalliita lääkkeitä. Säästyneet rahat olisi järkevä ohjata yllä mainittuihin toimiviin ennaltaehkäiseviin toimenpiteisiin.
9. Statiinien rooli sekundaaripreventiossa lienee täysin mahdollinen ja tärkeä. Statiinit vaimentavat tulehdusta ja laskevat LDL-kolesterolia, jolloin edistetään valtimon kykyä toipua taudista. Mutta miksi tyytyä valtimotaudin hoidossa haittavaikutuksia aiheuttaviin statiineihin kun on käytettävissä luonnollisempi hoitomuoto: anti-inflammatorinen ruoka, liikunta ja tupakoimattomuus.
10. Ehkä suurin epäkohta kolesteroliin liittyen on iäkkäiden ihmisten statiinien käyttö. Tutkimuksissa on ilmennyt, että iäkkäillä statiinien aiheuttamat terveyshaitat ovat moninkertaiset verrattuna nuorempiin. Miksi siis iäkkäitä ihmisiä rääkätään turhaan lukuisilla vakavilla terveyshaitoilla jotka vievät heiltä ainakin muistin ja liikuntakyvyn sekä aiheuttavat vakavia lihas- ja hermostosärkyjä? Minulla on tässä lista tutkimuksista missä todetaan, että korkea kolesteroli ei ole sydäntautien riskitekijä iäkkäillä ihmisillä. Päinvastoin, kolesteroli antaa suojaa iäkkäille. Ne vanhukset joilla on korkea kolesteroli elävät pisimpään:
    
    Ravnskov U and others. Ett statinpiller för mycket? Läkartidningen 43:2169-2171, 2011 (Sanningen är att mer än 20 studier har visat att äldre människor med högt kolesterol lever längst och att högt kolesterol inte är en riskfaktor för kvinnor.)
    Kozarevic D and others. Serum cholesterol and mortality: the Yugoslavia Cardiovascular Disease Study. Am J Epidemiol. 1981;114:21-28. (Serum cholesterol was negatively related to mortality, i.e., those with a lower cholesterol experienced a higher mortality than those with a higher cholesterol... Serum cholesterol, as expected, was positively related to the incidence of coronary heart disease death.)
    Rudman D and others. Antecedents of death in the men of a Veterans Administration nursing home. J Am Geriatr Soc 1987;35:496-502. (Multivariate analysis showed cholesterol and hematocrit to be the most informative of the eight mortality predictors and to correlate with death independently of age and functional level. Subgroups defined on the basis of combinations of mortality-related attributes differed many fold in their death rates. For example, men with cholesterol less than or equal to 156 mg/dl and hematocrit less than or equal to 41% died at a rate 42 times the rate of men with values above both thresholds. For each mortality-related attribute, death rate varied with the level of the attribute. This relationship extended into the generally accepted "normal ranges" for cholesterol, hematocrit, hemoglobin, and albumin.)
    Siegel D and others. Predictors of cardiovascular events and mortality in the Systolic Hypertension in the Elderly Program pilot project. Am J Epidemiol 1987;126:385-99. (These findings, combined with prior evidence, suggest that smoking, low education level, and perhaps serum cholesterol are risk factors for cardiovascular disease in the elderly. Although the excess risk conveyed by these factors is large, its reversibility needs to be demonstrated by intervention studies.)
    Forette B and others. Cholesterol as risk factor for mortality in elderly women. Lancet 1989;1:868-70. (Mortality was lowest at serum cholesterol 7.0 mmol/l, 5.2 times higher than the minimum at serum cholesterol 4.0 mmol/l, and only 1.8 times higher when cholesterol concentration was 8.8 mmol/l. This relation held true irrespective of age, even when blood pressure, body weight, history of myocardial infarction, creatinine clearance, and plasma proteins were taken into account. The relation between low cholesterol values and increased mortality was independent of the incidence of cancer.)
    Staessen J and others. Is a high serum cholesterol level associated with longer survival in elderly hypertensives? J Hypertens 1990;8:755-61. (Serum total cholesterol, measured at randomization, was independently and inversely correlated with total (P = 0.03), non-cardiovascular (P = 0.03) and cancer (P = 0.04) mortality during follow-up on double-blind treatment.)
    Harris T and others. The low cholesterol-mortality association in a national cohort. J Clin Epidemiol 1992;45:595-601. (However, the low serum cholesterol-mortality relationship was modified by time, age, and among older persons, activity level. The low serum cholesterol-mortality association was strongest in the first 10 years of followup. Moreover, this relationship occurred primarily among older persons (RR for low serum cholesterol for women 35-59 = 1.0 (0.6, 1.8), for women 70-74, RR = 2.1 (1.2, 3.7); RR for low serum cholesterol for men 35-59 = 1.2 (0.8, 2.0), for men 70-74, RR = 1.9 (1.3, 2.7)). Among older persons, however, the low serum cholesterol-mortality association was confined only to those with low activity at baseline. Factors related to underlying health status, rather than a mortality-enhancing effect of low cholesterol, likely accounts for the excess risk of death among persons with low cholesterol. The observed low cholesterol-mortality association therefore should not discourage public health programs directed at lowering serum cholesterol.)
    Casiglia E and others. Predictors of mortality in very old subjects aged 80 years or over. Eur J Epidemiol 1993;9:577-86. (Some well known risk factors (left ventricular hypertrophy, glucose intolerance, cholesterol, ApoB/ApoA ratio, triglycerides, proteinuria, cigarette smoking, and ECG abnormalities), whose importance in cardiovascular risk is definitely accepted for young adults, were very poor predictors of mortality in our survey.)
    Weverling-Rijnsburger AW and others. Total cholesterol and risk of mortality in the oldest old. Lancet 1997; 350:1119-1123. (In people older than 85 years, high total cholesterol concentrations are associated with longevity owing to lower mortality from cancer and infection. The effects of cholesterol-lowering therapy have yet to be assessed.)
    Jonsson A and others. Total cholesterol and mortality after age 80 years. Lancet 1997;350:1778-9. (As a biological factor, serum cholesterol is of decreasing importance as a risk factor for cardiovascular mortality with advancing years or up to age 80.)
    Räihä I, Marniemi J, Puukka P, Toikka T, Ehnholm C, Sourander L. Effect of serum lipids, lipoproteins, and apolipoproteins on vascular and nonvascular mortality in the elderly. Arterioscler Thromb Vasc Biol 1997;17:1224-32. (In the univariate analysis, a low total cholesterol level was associated with death due to both vascular and nonvascular causes (P value for trend, .021 and .0027, respectively). After the adjustment for other risk factors, the inverse association between total cholesterol and vascular mortality disappeared, but low total cholesterol was still a significant predictor of death due to nonvascular causes.)
    Behar S and others. Low total cholesterol is associated with high total mortality in patients with coronary heart disease. Eur Heart J 1997;18:52-9. (The relative risk of non-cardiac death was 2·27 times higher in the low cholesterol group than in the controls (95· CI: 1·49–3·45), whereas the risk of cardiac death was the same in both groups (relative risk 1·09; 95% CI: 0·76–1·56). The most frequent cause of non-cardiac death associated with low total cholesterol was cancer. These results in patients with coronary heart disease add weight to previous studies associating low total cholesterol with an increased risk of non-cardiac death. However, a longer follow-up of this cohort of patients is necessary in order to clarify this association.)
    Fried LP and others. Risk factors for 5-year mortality in older adults: the Cardiovascular Health Study. JAMA 1998;279:585-92. (Neither high-density lipoprotein cholesterol nor low-density lipoprotein cholesterol was associated with mortality. After adjustment for other factors, the association between age and mortality diminished, but the reduction in mortality with female sex persisted.)
    Chyou PH, Eaker ED. Serum cholesterol concentrations and all-cause mortality in older people. Age Ageing 2000;29:69-74. (A high level of high-density lipoprotein was significantly associated with a low total risk of mortality in older men. Conversely, an elevated ratio of total cholesterol to high-density lipoprotein was directly related to an increased total risk of mortality in older men. Age and high-density lipoprotein level had a significant synergistic effect on all-cause mortality for the elderly men. We found little or no association in women between all-cause mortality and any of the lipid measures studied. An increased ratio of total cholesterol to high-density lipoprotein appears to be associated with an increase in risk for all-cause mortality in men aged 65 and over, while an elevated level of high-density lipoprotein, considered alone, seems to be protective against mortality from all causes in men aged 65-74 years, but this effect diminishes over the age of 75.)
    Schatz IJ and others. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet 2001;358:351-5. (Mean cholesterol fell significantly with increasing age. Age-adjusted mortality rates were 68.3, 48.9, 41.1, and 43.3 for the first to fourth quartiles of cholesterol concentrations, respectively. Relative risks for mortality were 0.72 (95% CI 0.60-0.87), 0.60 (0.49-0.74), and 0.65 (0.53-0.80), in the second, third, and fourth quartiles, respectively, with quartile 1 as reference. A Cox proportional hazard model assessed changes in cholesterol concentrations between examinations three and four. Only the group with low cholesterol concentration at both examinations had a significant association with mortality (risk ratio 1.64, 95% CI 1.13-2.36). We have been unable to explain our results. These data cast doubt on the scientific justification for lowering cholesterol to very low concentrations (<4.65 mmol/L) in elderly people.)
    Weverling-Rijnsburger AW and others. High-density vs low-density lipoprotein cholesterol as the risk factor for coronary artery disease and stroke in old age. Arch Intern Med 2003;163:1549-54. (Both low LDL cholesterol and low HDL cholesterol concentrations were associated with an increased mortality risk of infection: 2.7 (95% CI, 1.2-6.2) and 2.4 (95% CI, 1.1-5.6), respectively. The risks were unaffected by comorbidity. In contrast to high LDL cholesterol level, low HDL cholesterol level is a risk factor for mortality from coronary artery disease and stroke in old age.)
    Onder G and others. Serum cholesterol levels and in-hospital mortality in the elderly. Am J Med 2003;115:265-71. (Among older hospitalized adults, low serum cholesterol levels appear to be an independent predictor of short-term mortality.)
    Casiglia E and others. Total cholesterol and mortality in the elderly. J Intern Med 2003;254:353-62. (High TC remains a strong risk factor for coronary mortality in elderly men. On the other hand, having a very low cholesterol level does not prolong survival in the elderly; on the contrary, low cholesterol predicts neoplastic mortality in women and any other noncardiovascular mortality in both genders.)
    Psaty BM and others. The association between lipid levels and the risks of incident myocardial infarction, stroke, and total mortality: The Cardiovascular Health Study. J Am Geriatr Soc 2004;52:1639-47. (For total cholesterol and LDL-C, the associations with MI and ischemic stroke were only marginally significant. HDL-C was inversely associated with MI risk (hazard ratio=0.85 per standard deviation of 15.7 mg/dL, 95% confidence interval=0.76-0.96). For the outcome of ischemic stroke, high levels of HDL-C were associated with a decreased risk in men but not women. Lipid measures were generally only weakly associated with the risks of hemorrhagic stroke or total mortality. In this population-based study of older adults, most lipid measures were weakly associated with cardiovascular events. The association between low HDL-C and increased MI risk was nonetheless strong and consistent.)
    Ulmer H and others. Why Eve is not Adam: prospective follow-up in 149650 women and men of cholesterol and other risk factors related to cardiovascular and all-cause mortality. J Womens Health 2004;13:41-53. (Patterns of cholesterol levels showed marked differences between men and women in relation to age and cause of death. The role of high cholesterol in predicting death from coronary heart disease could be confirmed in men of all ages and in women under the age of 50. In men, across the entire age range, although of borderline significance under the age of 50, and in women from the age of 50 onward only, low cholesterol was significantly associated with all-cause mortality, showing significant associations with death through cancer, liver diseases, and mental diseases. Triglycerides > 200 mg/dl had an effect in women 65 years and older but not in men. This large-scale population-based study clearly demonstrates the contrasting patterns of cholesterol level in relation to risk, particularly among those less well studied previously, that is, women of all ages and younger people of both sexes. For the first time, we demonstrate that the low cholesterol effect occurs even among younger respondents, contradicting the previous assessments among cohorts of older people that this is a proxy or marker for frailty occurring with age.)
    Schupf N. Relationship between plasma lipids and all-cause mortality in nondemented elderly. J Am Geriatr Soc 2005;53:219-26. (Low cholesterol level is a robust predictor of mortality in the nondemented elderly and may be a surrogate of frailty or subclinical disease. More research is needed to understand these associations.)
    Akerblom JL and others. Relation of plasma lipids to all-cause mortality in Caucasian, African-American and Hispanic elders. Age Ageing 2008;37:207-13. (Hispanics had the best overall survival, followed by African-Americans and Whites. Whites and African-Americans in the lowest quartiles of total cholesterol, non-HDL cholesterol and low-density lipoprotein cholesterol (LDL cholesterol) were approximately twice as likely to die as those in the highest quartile (White HR: 2.2, for lowest total cholesterol quartile; HR: 2.3, for lowest non-HDL cholesterol quartile; and HR: 1.8, for lowest LDL cholesterol quartile. African-American HR: 1.9, for lowest total cholesterol, HR: 2.0, for lowest non-HDL cholesterol and HR: 1.9, for lowest LDL cholesterol). In contrast, plasma lipid levels were not related to mortality risk among Hispanics. Hispanic ethnicity modifies the associations between lipid levels and all-cause mortality in the elderly.)
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