Cardiovascular Risk Factors: A Continuing Evolution
Friday, 26 December 2008 00:00
The clinical approach to cardiovascular disease has changed dramatically in the past few decades. That is in part due to the increased knowledge of the epidemiology of related risk factors and to a larger availability of qualified biomarkers for the diagnosis, treatment, and prevention of the disease. Several papers appeared recently which focus on specific issues regarding the impact and explanation for these changes.
First issue: the importance of population-based monitoring systems.
Within the last few decades there has been a decrease in mortality from CHD; despite this trend, CHD continues to be the leading cause of mortality and morbidity in many countries. Elevated blood cholesterol levels, cigarette smoking, high blood pressure, diabetes, metabolic syndrome, incorrect diet – all considered as consolidated risk factors – are now accompanied by inflammation, blood coagulation disorders, plaque instability, and alteration of autonomic tone of coronary vasculature (Circulation 2009;1109:1189-91). Additionally, during the same time frame, mortality from coronary artery disease (CHD) decreased by 60% (Circulation 2004;110:522-7; Circulation 1999:100:2054-9; NEJM 1998;339:861-7). Approximately half the decline in U.S. deaths from CHD from 1980 through 2000 may be attributed to reductions in major risk factors and approximately half to evidence-based medical therapies (N Engl J Med 356:2388-2398). Investigators of the Framingham Heart Study (FHS) have provided new insights into the explanation of the decrease of mortality, through the evaluation of data from a population of FHS men and women comparing data of long–term trends in myocardial infarction incidence (Circulation 2009;119:1203-10). The decrease of mortality is tied mostly to increased awareness of the importance of prevention and control of risk factors, especially hypertension, hypercholesterolemia, and smoking. Despite this, hospitalizations for acute myocardial infarction (AMI) remained stable over the past 20 years (NEJM 1998;339:861-7; Int J Epidemiol 2001;30(Suppl 1):S17-S22). The question is: how can a decrease in mortality from CHD and a concomitant stable rate of hospitalization for AMI be explained?
The authors speculated that this paradox can in part be explained by the increase of sensitive biomarkers for the diagnosis of AMI. The authors considered people enrolled in the Framingham study and compared the incidence and survival rates of initial AMI diagnosed by ECG (ECG-AMI) with the diagnosis made only with biomarkers (AMI-markers) over four decades: 1960-1969, 1970-1979, 1980-1989, and 1990-1999. In 9,824 people (54% female, aged between 40 and 89 years), there were 941 AMI, 639 of which were diagnosed with AMI-ECG and 302 AMI-markers. The markers of interest were: in the 1950s, the marker was GOT, while in the 1960s it was LDH; in the 1970s, CPK; in the 1980s, CPK-MB and isoenzymes of LDH; and in 1990s, troponin. After more than 40 years, the rate of AMI-ECG decreased by 50%, while the rate of AMI-marker has doubled. The investigators note the changes in both how AMI has been diagnosed over time and how information is collected in and out of the hospital. The findings reinforce the importance of reliance on population-based monitoring systems (Circulation 2009;119:1189-91).
Second issue: the growth of diabetes and of obesity are changing the medical scenario of cardiovascular disease.
Diabetes and obesity have long been accepted as major components within the total/global risk profile of cardiovascular disease (Lancet 2004; 364: 937–52. Lancet 2005;366:1640–9). How great is the burden of the two risk factors in the control of cardiovascular disease? Does the Framingham Heart Study (FHS), which is considered a fertile basic and dynamic source of information for researchers, provide us with an answer to the question? (Diabetes Care 2008;31:1367-72).
It is known that excess weight is associated with several cardiovascular disease risk factors: hypertension, dyslipidemia, diabetes, and metabolic syndrome. Recent data show that kidney disease is increasing and this increase is due in part to the growth of diabetes mellitus (JAMA 2007;298:2038-47) and unfortunately various therapies, lifestyle changes, and pharmacological interventions against obesity are often not effective (NEJM 2005;353:2111-20). Finally, bariatric surgery is an effective method to lose weight, but patients eligible for this method are the morbidly obese.
The investigators of Framingham Heart Study (FHS) evaluated the burden and rates of treatment and control of cardiovascular disease risk factors in obesity (Diabetes Care 2008;31:1367-72). The FHS is a population-based prospective cohort study started in 1948 with 5,209 men and women. In 1971, 5,124 men and women were enrolled into the Framingham Heart Study Offspring cohort, including the children of the original cohort and their spouses. Starting in 2002, 4,095 participants who had at least one parent in the Offspring cohort were enrolled into the Framingham Heart Third Generation Study. Every 4 years Offspring participants undergo examinations (Am J Epidemiol 2007;165:1328-35).
The purpose of this study was to examine, in an unselected population, impact, treatment, and control of risk factors in people with normal weight, in overweight people, and in obese people. The authors studied people in primary prevention (n = 6,801, mean age of 49 years, 54% women) who come from the Framingham Offspring and Third Generation participants who attended the seventh Offspring (1998-2001) or first Third Generation (2002-2005) examination cycle, respectively. The results were as follows: obese people have been subjected to more antihypertensive treatment (62.3%) than people of normal weight (58.7%) and overweight people (59%), but no difference was observed in the control of hypertension (36.7% in normal weight, overweight in 37.3%, 39.4% obese). The number of people receiving lipid lowering treatment was greater in those who were obese (39.5%) compared with normal weight (34.2%) and overweight (36.5%). No difference was seen in the treatment of diabetes (69.2% in normal weight, 50% in overweight, 55% obese). The data emphasize a suboptimal treatment and suboptimal control of risk factors among overweight and obese people. Rates of dual and triple control of CVD risk factors were uniformly poor across BMI categories in the study sample. The data emphasize the importance of a treatment regimen aimed at controling multiple risk factors. “Without substantial improvements in CVD risk factor treatment and control rates among obese individuals, the medical and financial burden of CVD events may grow substantially in the next several decades” (Diabetes Care 2008; 31:1367-72).
Third issue: LDL-C and HDL-C measurement or ApoB/ApoA1 ratio?
Reliable assessment of coronary heart disease (CHD) and ischemic stroke is the basis of an effective approach to primary and secondary prevention of vascular diseases. How well established is the use of markers for dyslipidemia?
In spite of the ample use of disease markers, critical issues in risk assessment are still open. For example, there is no common acceptance of the use of apolipoproteins B and AI, and their ratio, in lieu of the more traditional approach of LDL-C and HDL measurement (JACC 2008;51:1512-24). The INTERHEART study (Lancet 2004;364:937-52) showed that the same nine modifiable risk factors (smoking, exercise, fruit and vegetable intake, alcohol consumption, hypertension, diabetes, abdominal obesity, psychosocial, high apolipoprotein B100 (ApoB)/apolipoprotein A1 (ApoA1) ratio) accounted for almost all the population-attributable risk (PAR) of myocardial infarction and that these same factors applied to all the major population groups in the world. Of these risk factors, the ApoB/ApoA1 ratio—an index of the proatherogenic and antiatherogenic lipoproteins in plasma—accounted for half the PAR. “In combination, the largest trials (INTERHEART Lancet 2004;364:937-52 and AMORIS Lancet 2001;358:2026-33) point out an advantage of the apolipoprotein B/A1 ratio over traditional lipid variables for risk prediction, although divergent results have been obtained in smaller studies. Apolipoproteins can be measured in a standardised and automatic manner at a cost close to assay of traditional lipid variables and also in the non-fasting state. Although wide-scale introduction of apolipoprotein assay in clinical practice would possibly improve risk prediction to some degree, the most important task is to ascertain that lipids are evaluated at all. Physicians and patients have taken decades to learn to measure lipids and treat hyperlipidaemia, and it will be a demanding but not impossible task of education to substitute traditional lipid measurements by the possibly somewhat better apolipoproteins” (Lancet 2008;372:185-86).
“The non-fasting ApoB/ApoA1 ratio was superior to any of the cholesterol ratios for estimation of the risk of acute myocardial infarction in all ethnic groups, in both sexes, and at all ages, and it should be introduced into worldwide clinical practice” (Lancet 2008;372:224-33).
In an analysis of more than 300,000 people, the Emergency Risk Factors Collaboration (ERFC) investigators have demonstrated that lipid assessment in vascular disease can be simplified by measurement of either cholesterol levels or apolipoproteins without the need to fast and without regard to triglyceride (JAMA 2009;302:1993-2000). In that analysis, the hazard ratios (HRs) with non-HDL-C and HDL-C were nearly identical to those seen with apo B and apo AI. “This finding suggests that current discussions about whether to measure cholesterol levels or apolipoproteins in vascular risk assessment should hinge more on practical considerations (e.g. cost, availability, and standardization of assays) than on major differences in strength of epidemiological associations.” Another conclusion by the analysis was that HRs for vascular disease with lipid levels were at least as strong in fasting and not fasting subjects who did not fast, as in those who fasted. HRs with non–HDL-C were similar to those measured by LDL-C. Triglyceride measurement provided no additional information about vascular risk given by HDL-C and total cholesterol levels: other reasons can justify the measurement of triglyceride concentration, such as the prevention of pancreatitis (see also JAMA 2007;298:309-16 and JAMA 2007;298:299-308). The analysis did not demonstrate any correlation between hemorrhagic stroke and any of the lipids studied. Pro-atherogenic lipids are modestly associated with risk of ischemic stroke, while they are about 4 times associated with CHD. “Because statin medications reduce risk of both CHD and ischemic stroke to a similar extent, (Lancet 2005;366:1267-78) the quantitative discrepancy observed between epidemiological associations of non-HDL-C with CHD and ischemic stroke is striking (BMJ 2003;326:1423). To characterize this risk in more detail, studies are needed that can subtype the diverse etiologies for ischemic stroke” (Neurology 2004;63:1868-75).
Fourth Issue: Lp(a): the shift from a curiosity to a causal CHD risk factor.
In spite of many studies supporting a better understanding of lipoprotein(a) (Lp(a)) in the pathophysiology of coronary disease (CHD), the molecule has been considered by some researchers rather a curiosity than a causal CVD risk factor. New genetic research is readdressing the attention of researchers and confirming that Lp(a) could be considered a casual factor for coronary disease (N Engl J Med 2009;361:2518-28).
Lp(a) lipoprotein, which was initially described in 1963 by Kåre Berg (A new serum type system in man — the Lp system. Acta Pathol Microbiol Scand 1963;59:369-82) is a circulating macromolecule consisting of a low-density lipoprotein (LDL) particle that is covalently linked to a protein called apolipoprotein(a). Plasma Lp(a) lipoprotein has long been proposed as a risk factor for coronary artery disease (Acta MedScand Suppl 1972;531:1-29). However, it has long been debated whether an elevated plasma level of Lp(a) lipoprotein is the cause or the consequence of coronary artery disease (N Engl J Med 2009;361:2573-74). A step forward was made with the development of reliable measurement methods used to better understand the relationship between the number of apolipoprotein (a) kringle 4 repeats basis for a standardized isoform nomenclature (Clin Chem1996;42:436-9), and to determine the relative number of LPA kringle IV–type 2 repeats in a subgroup of subjects for whom isoform data were available (J Lipid Res 2009;50:768-72). Another step forward has been made by the proposal (by the International Federation of Clinical Chemistry and Laboratory Medicine) to use the same reference-certified material in the detection of Lp(a) in plasma (Clin Chem 2000;46:1956-67). Although identification of the functional role of Lp(a) in atherogenesis has been thwarted by the physical, chemical, and genetic complexity of Lp(a), the structural similarity of Lp(a) to both the fibrinolytic proenzyme plasminogen and low-density lipoprotein (LDL) has suggested a prothrombotic or atherogenic role (or both) for this lipoprotein. (http://www.cababstractsplus.org/abstracts/Abstract.aspx?AcNo=20043162813). Evidence mounts for the role of the kidney in lipoprotein(a) catabolism (Kidney Int 2007;71:961-2).
There are independent continuous associations between Lp(a) levels and risk of future CHD in a broad range of individuals. Levels of Lp(a) are highly stable within individuals over time and are only weakly correlated with known risk factors (Arch Intern Med. 2008;168:598-608).
The Emerging Risk Factors Collaboration Group (more than 250 researchers led by Sebhat Erqou, Stephen Kaptoge, Philip L. Perry, Emanuele Di Angelantonio, Alexander Thompson, Ian R. White, Santica M. Marcovina, Rory Collins, Simon G. Thompson, John Danesh) completed a study of long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality and were published between January 1970 and March 2009 (JAMA 2009;302:412-23). Individual records were provided for each of 126,634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22,076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9,336 CHD outcomes, 1,903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1,091 other vascular deaths, 8,114 nonvascular deaths, and 242 deaths of unknown cause. Lipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years Associations of Lp(a) with CHD risk were broadly continuous in shape. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per 3.5-fold higher usual Lp(a) concentration (i.e. per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate of nonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) for nonvascular deaths other than cancer. Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.
Genome-wide association studies of plasma lipoprotein(a) have been conducted on many occasions (J Med genet 2006; 43 812: 917-923; J Lipid Res 2009; 50: 798-806). Recently associations with 77 single nucleotide polymorphisms (SNPs) spanning 12.5 Mb on chromosome 6q26-q27 that met criteria for genome-wide significance (P < or = 1.3 x 10(-7)) and were within or flanking nine genes, including LPA, have been published (J Lipid Res 2009 May;50(5):798-806). Variation in at least six genes in addition to LPA are significantly associated with Lp(a) levels independent of each other and of the kringle IV repeat polymorphism in the LPA gene. One novel SNP in intron 37 of the LPA gene was also associated with Lp(a) levels and carotid artery disease number in unrelated Caucasians (P = 7.3 x 10(-12) and 0.024, respectively), also independent of kringle IV number. Those data suggest a complex genetic architecture of Lp(a) levels that may involve multiple loci on chromosome 6q26-q27.
A more recently published study provides convincing support for the notion that plasma Lp(a) levels causally relate to coronary disease (N Engl J Med 2009;361:2518-28). Two relatively rare single nucleotide polymorphisms (SNPs) have been identified, which are able to explain a third of the variance in lipoprotein(a) levels in individuals of European descent. The work confirms unequivocally that Lp(a) is a causal factor for coronary disease. The case–control study, called the Precocious Coronary Artery Disease (PROCARDIS) study a) examined genetic associations in coronary artery disease, using a newly available chip13 that was specifically designed to assay SNPs in candidate genes selected for their putative relevance to cardiovascular disease; b) assessed the associations of LPA gene variants with Lp(a) lipoprotein levels and isoform size in a large case–control study; c) replicated the associations in three independent studies; d) assessed the extent to which the observed associations were explained by their effects on Lp(a) lipoprotein levels. No significant association between either rs10455872 or rs3798220, and the plasma level of apolipoprotein B, fibrinogen, or C-reactive protein.
By contrast the two-SNP LPA genotype score explained 36% of the variation in the Lp(a) lipoprotein level, and the association between LPA and the risk of coronary disease was abolished after adjustment for the Lp(a) lipoprotein level in a meta-analysis of 3,137 subjects with coronary disease — findings that are consistent with a causal role of an increased Lp(a) lipoprotein level in coronary disease. In conclusion two common SNPs in LPA have been identified to correlate with both the Lp(a) lipoprotein level and the risk of coronary disease. These SNPs explain 36% of the variation in the Lp(a) lipoprotein level. One in six persons carries a variant LPA allele and thus has a risk of coronary disease that is increased by a factor of 1.5.
December 26, 2009
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