Independent Cardiovascular Disease Risk Research Articles

Abstract 1094: Inflammation Results In Increased Allele-specific Apo(a) Levels In African Americans: Potential Explanation For Inter-ethnic Difference?

Background: The role of inflammation in the pathogenesis of cardiovascular disease (CVD) is well recognized. Lipoprotein(a), Lp(a), is an independent CVD risk factor where plasma levels are largely determined by apo(a) gene size. Allele-specific apo(a) levels are higher among African Americans (AA) compared to Caucasians (C), and the most pronounced inter-ethnic difference is seen for medium-sized apo(a) alleles. This difference remains unexplained. The apo(a) gene contains response elements for inflammatory factors. However, the effect of inflammation on Lp(a) level, particularly on allele-specific apo(a) levels is unknown. Objective: We investigated the effect of inflammation measured by two acute-phase reactants (CRP and fibrinogen) on allele-specific apo(a) levels in AA and C. Methods: We determined Lp(a) levels, apo(a) sizes, allele-specific apo(a) levels, fibrinogen and CRP levels in 167 AA and 259 C. Results: Lp(a) levels were increased among AA with higher vs. lower CRP (>3 mg/dl) or fibrinogen (>340 mg/dl) levels (143 vs. 108 nmol/l, P =0.009, and 146 vs. 105 nmol/l, P =0.002, respectively). We next analyzed allele-specific apo(a) levels for different apo(a) sizes. No differences in allele-specific apo(a) levels across CRP (>3 vs. ≤3 mg/dl) or fibrinogen (>340 vs. ≤340 mg/dl) groups were seen among AA or C for small apo(a) sizes (<22 K4). Allele specific apo(a) levels for medium apo(a) sizes (23–30 K4) were significantly higher among AA with high levels of CRP or fibrinogen compared to those with low levels (88 vs. 67 nmol/l, P =0.014 and 91 vs. 59 nmol/l, P< 0.0001, respectively). In contrast, there were no significant differences in allele-specific apo(a) levels across CRP or fibrinogen groups among C with medium sized apo(a) alleles. Conclusion: Increased levels of CRP or fibrinogen are associated with higher allele-specific medium-sized apo(a) levels in AA, but not in C. Our results implicate that a pro-inflammatory stimulus may result in a selective increase in Lp(a) levels among AA carrying medium-sized apo(a). These findings provide a potential explanation for differences in Lp(a) levels between African Americans and Caucasians and suggest that inflammation-associated events may contribute to this inter-ethnic difference.

Bone health and vascular calcification relationships in chronic kidney disease

Abnormal bone in chronic kidney disease (CKD) may adversely affect vascular calcification via disordered calcium and phosphate metabolism. In this context, bone health should be viewed as a prerequisite for the successful prevention/treatment of vascular calcification (VC) along with controlled parathyroid hormone (PTH) secretion, the use of calcium-based phosphate binders and vitamin D therapy. In CKD patients, VC occurs more frequently and progresses more rapidly than in the general population, and is associated with increased cardiovascular disease (CVD) morbidity and mortality. A number of therapies aimed at reducing PTH concentration are associated with an increase of calcaemia and Ca x P product, e.g. calcium-containing phosphate binders or active vitamin D. The introduction of calcium-free phosphate binders has reduced calcium load, attenuating VC and improving trabecular bone content. In addition, a major breakthrough has been achieved through the use of calcimimetics, as first agents which lower PTH without increasing the concentrations of serum calcium and phosphate. Nowadays, it is becoming evident that even early stage CKD is recognised as an independent CVD risk factor. Moreover, the excess of CVD among dialysis patients cannot be explained entirely on the basis of abnormal mineral and bone metabolism. Hence, much controversy has surrounded the cost-effectiveness of treatment with the new phosphate-binding drugs as well as new vitamin D analogs and calcimimetics. Thus, it seems prudent and reasonable that maintaining bone health and mineral homeostasis should rely on some modifications of standard phosphate binding and calcitriol therapy. Hypophosphataemia and hypercalcaemia in adynamic bone disease (ABD) might be treated by reducing the number of calcium carbonate/acetate tablets in order to increase serum phosphate and decrease serum calcium, which, in turn, might positively stimulate PTH secretion. The same rationale is assumed for the use of a low calcium dialysate. On the other hand, secondary hyperparathyroidism with hyperphosphataemia and hypocalcaemia should be treated with a substantial number of calcium carbonate/acetate tablets in combination with calcitriol and low calcium dialysate in order to decrease serum phosphate and maintain the Ca x P product within K/DOQI guidelines (<4.4 mmol l(-1)). Finally, it becomes apparent that prevention, with judicious use of calcium-based binders, vitamin D and a low calcium dialysate without adverse effects on Ca x P or oversuppression of PTH, provides the best management of VC and mineral and bone disorder in CKD patients.

Increased prevalence of ventricular fibrillation in patients with type 2 diabetes mellitus

Diabetes mellitus (DM) is an independent risk for cardiovascular disease. Furthermore, patients with DM have increased risk for ventricular arrhythmia that is thought to be secondary to coronary artery disease (CAD) or congestive heart failure (CHF). We hypothesized that DM may cause ventricular arrhythmias independent of CAD or CHF. Using a large database, we evaluated the occurrence of ventricular fibrillation in patients with DM adjusting for CAD and CHF. We used patient treatment files (PTF), documents of inpatients' admissions containing discharge diagnoses (ICD-9 codes) from all Veterans Health Administration Hospitals. The patients were stratified in two groups: ICD-9 code for DM (293 124) and a control group with ICD-code for hypertension (HTN) but no DM (552 623). ICD-9 codes for ventricular fibrillation were used for this study. We performed uni- and multivariant analysis adjusting for comorbid conditions. Ventricular fibrillation was present in 563 (0.2%) vs 781 (0.1%) in the control group. Using multivariate analysis, DM remained independently associated with ventricular fibrillation (odds ratio: 1.7; confidence interval: 1.5-1.9; P < 0.000). Patients with DM have significantly higher prevalence of ventricular fibrillation independent of CAD or CHF, which in part may explain the higher risk of sudden death in patients with DM.

Cardiovascular risk of systolic versus diastolic blood pressure in Western and non-Western countries

Cardiovascular risk of systolic versus diastolic blood pressure in Western and non-Western countries

The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients

To determine the contribution of classical risk factors to the development of cardiovascular disease (CVD) in patients with heterozygous familial hypercholesterolaemia (FH). A retrospective, multi-centre, cohort study. Extensive data were collected by scrutinizing medical records and the use of questionnaires. Multivariate Cox regression was used to study the relationship between potential risk factors and the occurrence of CVD. We included 2400 FH patients from 27 Dutch lipid clinics. The diagnosis of FH was based upon the presence of a low-density lipoprotein receptor mutation or upon strict clinical criteria. Cardiovascular mortality and CVD. During 112.943 person-years, 782 (32.6%) patients had had at least one cardiovascular event. Male gender (RR 2.82, 95% CI 2.37-3.36), smoking (RR 1.67, 95% CI 1.40-1.99), hypertension (RR 1.36, 95% CI 1.06-1.75), diabetes mellitus (RR 2.19, 95% CI 1.36-3.54), low HDL-C (RR 1.37, 95% CI 1.15-1.63) and elevated lipoprotein(a) levels (RR 1.50, 95% CI 1.20-1.79) proved to be independent CVD risk factors. These six risk factors explained 18.7% of the variation in the occurrence of CVD. Male gender, smoking, hypertension, diabetes mellitus, HDL cholesterol and lipoprotein(a) levels proved to be important risk factors for CVD in FH patients. In addition to the routine institution of statin therapy, controlling these factors needs special attention in the management of this disorder.

Low circulating vitamin B(6) is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels.

Lower vitamin B(6) concentrations are reported to confer an increased and independent risk for cardiovascular disease (CVD). The mechanism underlying this relationship, however, remains to be defined. Other diseases, such as rheumatoid arthritis, are associated with reduced vitamin B(6) levels. Despite a clear distinction in pathophysiology, inflammatory reaction may be the major link between these diseases. We hypothesized a relationship between pyridoxal 5'-phosphate (PLP), the active form of vitamin B(6), and the marker of inflammation C-reactive protein (CRP). We also evaluated whether total plasma homocysteine (tHcy), a well-defined risk factor for CVD and a major determinant of plasma PLP levels, had a possible role as a mediator of this hypothesized relationship. Data from 891 participants from the population-based Framingham Heart Study cohort were analyzed. Subjects were divided into 2 groups according to normal or elevated CRP values: group 1, CRP <6 mg/L; group 2, CRP >/=6 mg/L. Plasma PLP levels were substantially lower in group 2 than in group 1 (mean values in group 2, 36.5 nmol/L versus 55.8 nmol/L in group 1, P<0.001). In a multiple logistic regression model adjusted for tHcy, the association of PLP with CRP remained highly significant (P=0.003). Low plasma PLP is associated with higher CRP levels independently of tHcy. This observation may reflect a vitamin B(6) utilization in the presence of an underlying inflammatory process and represent a possible mechanism to explain the decreased vitamin B(6) levels in CVD.

Independent risk for cardiovascular disease predicted by modified continuous score electrocardiographic criteria for 6-year incidence and regression of left ventricular hypertrophy among clinically disease free men: 16-year follow-up for the multiple risk factor intervention trial

Risk prediction for electrocardiographic (ECG) left ventricular hypertrophy related criteria, used in clinical trials, and epidemiologic studies of clinically healthy people, has depended in the past on dichotomous classification of ECG LVH criteria. Recent analyses have shown that more sensitive methods of LVH ECG classification without loss of specificity are needed to improve on dichotomous classification. This was done by relating six year incident significant change in continuous score criteria of ECG LVH to the 16 year (10 year post trial) coronary heart disease (CHD) and cardiovascular disease (CVD) mortality among 12,866 men, free of clinical disease, aged 35 to 57 years at baseline in the Multiple Risk Factor Intervention Trial. It was found that significant change in continuous ECG LVH criteria was a stronger independent predictor of future CHD and CVD mortality than was use of dichotomous classification of the same criteria. It was also demonstrated that increase in continuous ECG LVH indexes, below previous dichotomous thresholds independently (of standard CVD risk factors, including increase in obesity—indicated by an increase in adult BMI) predicted excess CHD and CVD mortality and that combinations of continuous indices increases the specificity and relative risk in clinically disease-free middle-aged men.

Hyperhomocysteinemia in chronic renal failure patients: relation to nutritional status and cardiovascular disease.

A moderate increase in plasma total homocysteine (tHcy) is considered to be an independent risk factor for cardiovascular disease (CVD) in the general population. Almost all chronic renal failure (CRF) patients have plasma concentration of tHcy that is elevated 3 to 4 times above normal. The prevalence of CVD, diabetes mellitus, malnutrition and hypoalbuminemia is high in CRF patients. Previous investigations have focused on the role of vitamin status on plasma tHcy in CRF patients, but little information exists on the influence of nutritional status and hypoalbuminemia on plasma tHcy in CRF, although a substantial fraction of tHcy (>70%) is protein-bound, mainly to albumin. Our study in patients with end-stage renal disease showed that more than 90% of the patients had elevated plasma tHcy levels, which were higher in patients with normal nutritional status than in malnourished patients. Moreover, plasma tHcy was inversely correlated with subjective global nutritional assessment (high values denote malnutrition) and positively correlated with serum albumin and protein intake. Hence, it seems likely that serum-albumin is a strong determinant of plasma tHcy in CRF patients and this may contribute to the lower tHcy levels in malnourished patients. Patients with diabetes mellitus had lower serum-albumin and plasma tHcy than non-diabetic patients, irrespective whether they were malnourished or not. Patients with CVD had lower (although still elevated) plasma tHcy levels than those without CVD. An explanation may be that the prevalence of diabetes mellitus, malnutrition and hypoalbuminema, i.e. factors that decrease tHcy, was higher in patients with CVD, which may explain why they had less elevated values. Assuming that hyperhomocysteinemia carries an independent risk of CVD, this implies that almost all CRF patients are exposed to this risk. CRF patients with CVD had a higher prevalence of malnutrition, hypoalbuminemia and diabetes mellitus, which was associated with a lower plasma Hcy level. This may explain why plasma tHcy was lower (although still abnormally high) in patients with CVD than in patients without CVD. The lower tHcy levels in CVD patients do not contradict the assumption that hyperhomocysteinemia is a risk factor for CVD since almost all patients are exposed to this risk, and other factors might be present that confound the relationship between the absolute tHcy levels and CVD. Our findings imply that nutritional status and serum albumin, as well as the presence of diabetes mellitus, should be taken into consideration when evaluating tHcy as a risk factor for CVD in CRF patients.

Atherosclerosis, thrombosis and inflammation: a problem of linkage

Summary Cardiovascular disease (CVD) is in part an inflammatory process, although our traditional definitions of inflammation may need modification. Hallmarks of this ‘new’ inflammation include: (a) a chronic, low-level nature, (b) often an apparent lack of immunological activation, (c) elaboration of cytokines such as IL-6, (d) chronic, often mild, elevations of so-called ‘acute phase reactants’, (e) an intricate relation to smoking history, and (f) a strong relation to fibrinolytic activity. Several ‘acute phase’ markers have been identified as independent CVD risk factors, including fibrinogen, C-Reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1), and several others. There are many potential mechanisms by which these factors may contribute to the atherothrombotic process, and the prospective nature of some analyses has been used to argue that these factors are in the causal pathway for CVD. However, these results are confounded by subclinical disease, which is both a strong causal factor for CVD and the inflammatory stimulus. Ongoing studies in which cases and controls are matched on extent of subclinical disease, eliminate this confounding. It appears likely that genetic elevations may predispose towards atherothrombosis. In the absence of genetic elevations, if atherothrombosis progresses, inflammation will cause elevations. These elevations, in turn, may accelerate the process. In this sense, elevated acute phase markers are both a cause and a consequence of CVD.

Management of Hypertension: A Bangladeshi Perspective

Hypertension is a silent killer. Bangladeshis are racially predisposed to cardiovascular disease, and the increasing burden of hypertension has only added to the problem. Economic constraints and the allure of additional benefits without adverse effects have made lifestyle modifications an attractive proposition in developing and developed countries alike. Blood pressure is a continuum and any increase above optimum level confers additional independent risk of cardiovascular disease. We review screening, diagnosis and management using lifestyle measures and pharmacotherapy. We then discuss the barriers and challenges to implementing this approach and what can be done regarding prevention, screening, lifestyle modification and pharmacotherapy in our country. By adopting a comprehensive population based approach including policy level interventions directed at promoting lifestyle changes; a healthy diet (appropriate calories, low in saturated fats and salt and rich in fruits and vegetables), increased physical activity, and a smoking free society, properly balanced with a high risk approach of cost effective clinical care, Bangladesh can effectively control hypertension and improve public health. DOI: 10.3329/bmj.v39i1.6232 Bangladesh Medical Journal 2010; 39(1): 40-43