C-reactive protein and coronary heart disease: a critical review.

Modestly elevated baseline concentrations of C-reactive protein (CRP), the classical acute phase protein, are associated with the long-term risk of coronary heart disease in general populations, whilst the major acute phase response of CRP following myocardial infarction is associated with death and cardiac complications. The pathogenic and clinical significance of these associations is controversial. Here we critically review the evidence and describe large-scale epidemiological studies, novel experiments and possible specific therapies which will rigorously inform the debate. We distinguish between the potential pathogenicity of high acute phase circulating CRP concentrations in individuals with substantial tissue damage and modest but persistent increases in baseline values in generally healthy subjects.

Disease-associated prion protein is not detectable in human systemic amyloid deposits.

Cerebral and cardiac amyloid deposits have been reported after scrapie infection in transgenic mice expressing variant prion protein (PrP(C)) lacking the glycophosphatidylinositol anchor. The amyloid fibril protein in the systemic amyloid deposits was not characterized, and there is no clinical or pathological association between prion diseases and systemic amyloidosis in humans. Nevertheless, in view of the potential clinical significance of these murine observations, we tested both human amyloidotic tissues and isolated amyloid fibrils for the presence of PrP(Sc), the prion protein conformation associated with transmissible spongiform encephalopathy (TSE). We also sequenced the complete prion protein gene, PRNP, in amyloidosis patients. No specific immunohistochemical staining for PrP(Sc) was obtained in the amyloidotic cardiac and other visceral tissues of patients with different types of systemic amyloidosis. No protease-resistant prion protein, PrP(res), was detectable by Western blotting of amyloid fibrils isolated from cardiac and other systemic amyloid deposits. Only the complete normal wild-type PRNP gene sequence was identified, including the usual distribution of codon 129 polymorphisms. These reassuringly negative results do not support the idea that there is any relationship of prions or TSE with human systemic amyloidosis, including cardiac amyloid deposition.

Organ transplantation in hereditary apolipoprotein AI amyloidosis.

Patients with hereditary apolipoprotein AI (apoAI) amyloidosis often have extensive visceral amyloid deposits, and many develop end-stage renal failure as young adults. Solid organ transplantation to replace failing organ function in systemic amyloidosis is controversial due to the multisystem and progressive nature of the disease and the risk of recurrence of amyloid in the graft. We report the outcome of solid organ transplantation, including dual transplants in 4 cases, among 10 patients with apoAI amyloidosis who were followed for a median (range) of 16 (4-28) and 9 (0.2-27) years from diagnosis of amyloidosis and transplantation, respectively. Eight of 10 patients were alive, seven with a functioning graft at censor. Two patients died, one of disseminated cytomegalovirus infection 2 months after renal transplantation and the other of multisystem failure following severe trauma more than 13 years after renal transplantation. The renal transplant of one patient failed due to recurrence of amyloid after 25 years. Amyloid disease progression was very slow and the natural history of the condition was favorably altered in both cases in which the liver was transplanted. Failing organs in hereditary apoAI amyloidosis should be replaced since graft survival is excellent and confers substantial survival benefit.

Relationship of granulocyte colony stimulating factor with other acute phase reactants in man.

The non-specific acute phase response in mice is associated with increased resistance to bacterial infection, which is critically mediated by granulocyte colony stimulating factor (G-CSF), but the behaviour of G-CSF in the human acute phase response is not known. Cardiothoracic surgery is a powerful acute phase stimulus and we show here that this procedure caused increased production of G-CSF, in addition to increases in the circulating concentrations of the proinflammatory cytokine interleukin (IL)-6 and the acute phase plasma proteins C-reactive protein (CRP) and serum amyloid A protein (SAA). Values of G-CSF correlated positively with IL-6 concentrations and circulating neutrophil counts, but not with CRP values. These results confirm that G-CSF is a physiological component of the acute phase response in humans that shares some of the same regulatory controls as IL-6, but its downstream effects are on neutrophils, not hepatic acute phase protein synthesis. Our observations are compatible with a protective role against bacterial infection for G-CSF in the human acute phase response, and support investigation of the prophylactic use of G-CSF in at-risk patients.

Preprocedural inflammatory markers do not predict restenosis after successful coronary stenting.

BACKGROUND: Levels of C-reactive protein (CRP), serum amyloid A protein (SAA), and interleukin-6 (IL-6) can predict coronary restenosis following angioplasty and stent deployment in patients with unstable angina. We investigated whether measurement of periprocedural inflammatory markers predicted the angiographic outcome at 6 months in stable angina patients undergoing coronary stenting. METHODS: We prospectively studied 182 patients; 152 patients underwent elective and successful stenting procedure for de novo lesions in native and nongrafted coronary arteries and 30 individuals in the control group underwent diagnostic angiography alone. CRP, SAA, and IL-6 were determined by high-sensitivity immunoassays. RESULTS: At 6 months, quantitative computer-assisted angiographic analysis in 133 patients with stents showed a binary restenosis rate of 33.8%. Statins were being taken by 80% of the patients. There were no significant differences between the pre- or postprocedure values of CRP, SAA, or IL-6 in patients with or without in-stent restenosis. CONCLUSIONS: Preprocedural inflammatory markers in stable angina subjects undergoing coronary artery stent deployment did not correlate with the development of in-stent restenosis. Differences in pathobiology between stable and unstable coronary syndromes, the widespread use of statins with anti-inflammatory activity in our cohort of patients, along with different mechanisms underlying the early angiographic appearances of restenosis as compared to clinical end points, most likely explain our findings.

C-reactive protein and cardiovascular disease: new insights from an old molecule.

The classical acute-phase protein, C-reactive protein (CRP), is an exquisitely sensitive systemic marker of disease with broad clinical utility for monitoring and differential diagnosis. Inflammation, the key regulator of CRP synthesis, plays a pivotal role in atherothrombotic cardiovascular disease. There is a powerful predictive association between raised serum CRP values and the outcome of acute coronary syndromes, and, remarkably, between even modestly increased CRP production and future atherothrombotic events in otherwise healthy individuals. Baseline CRP values also reflect metabolic states associated with atherothrombotic events. The presence of CRP within most atherosclerotic plaques and all acute myocardial infarction lesions, coupled with binding of CRP to lipoproteins and its capacity for pro-inflammatory complement activation, suggests that CRP may contribute to the pathogenesis and complications of cardiovascular disease. We review the biological properties of CRP, the association between CRP and cardiovascular disease, and the possibility that CRP may be a novel therapeutic target.

The structures of crystalline complexes of human serum amyloid P component with its carbohydrate ligand, the cyclic pyruvate acetal of galactose.

Two monoclinic (P2(1)) crystal forms of human serum amyloid P component (SAP) in complex with the 4,6-pyruvate acetal of beta-D-galactose (MObetaDG) were prepared. Structure analysis by molecular replacement and refinement at 2.2A resolution revealed that crystal form 1 (a=95.76A, b=70.53A, c=103.41A, beta=96.80 degrees) contained a pentamer in the asymmetric unit with a structure very similar to that of the published search model. The mode of ligand co-ordination was also similar except that four of the five subunits showed bound ligand with an additional H-bond between O1 of the galactose and the side-chain of Lys79. One sub-unit showed no bound ligand and a vacant calcium site close to a crystal contact. The 2.6A resolution structure of crystal form 2 (a=118.60A, b=109.10A, c=120.80A and beta=95.16 degrees ) showed ten sub-units in the asymmetric unit, all with two bound calcium ions and ligand. The most extensive protein-protein interactions between pentamers describe an AB face-to-face interaction involving 15 ion pairs that sandwiches five molecules of bound MObetaDG at the interface.

Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis.

The normal plasma protein serum amyloid P component (SAP) binds to fibrils in all types of amyloid deposits, and contributes to the pathogenesis of amyloidosis. In order to intervene in this process we have developed a drug, R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, that is a competitive inhibitor of SAP binding to amyloid fibrils. This palindromic compound also crosslinks and dimerizes SAP molecules, leading to their very rapid clearance by the liver, and thus produces a marked depletion of circulating human SAP. This mechanism of drug action potently removes SAP from human amyloid deposits in the tissues and may provide a new therapeutic approach to both systemic amyloidosis and diseases associated with local amyloid, including Alzheimer's disease and type 2 diabetes.

Unicentric Castleman's disease complicated by systemic AA amyloidosis: a curable disease.

BACKGROUND: Castleman's disease (angiofollicular lymph node hyperplasia) is a group of rare lymphoproliferative disorders sharing characteristic clinical and histological features, and usually accompanied by a marked systemic inflammatory response. All types may be complicated by acquired systemic amyloidosis, usually of AA type, but occasionally of AL type associated with monoclonal gammopathy. DESIGN: Descriptive study of five patients with unicentric Castleman's disease complicated by systemic AA amyloidosis. METHODS: A diagnosis of amyloidosis was confirmed by microscopy and immunohistochemical staining. Serum concentrations of C-reactive protein (CRP) and serum amyloid A protein (SAA) were measured by immunoassays. Radiolabelled serum amyloid P component scintigraphy was used to monitor the progress of amyloid deposition. RESULTS: In four patients the primary diagnosis was made only after years of investigation of systemic symptoms. The tumours were resected in all cases, leading to remission of the systemic inflammatory state. Long-term follow-up in four patients, including scintigraphy, showed regression of amyloid deposits. DISCUSSION: This rare but usually fatal condition can be cured surgically even in advanced cases. Awareness of the diagnosis and its correct management are important in investigation of patients with unexplained systemic symptoms, especially associated with systemic amyloidosis.

Particulate air pollution is associated with an acute phase response in men; results from the MONICA-Augsburg Study.

AIMS: Episodes of increased air pollution are associated with increases in hospital admissions for cardiovascular disease. Even modest acute phase responses are associated with increased risk of coronary heart disease. The study investigates whether induction of an acute phase response by exposure to air pollution may contribute to cardiovascular pathology. METHODS AND RESULTS: A prospective cohort study based on a survey in 1984/85 with a 3-year follow-up was conducted in 631 randomly selected men aged 45 to 64 years free of cardiovascular disease at entry 1984/85. Serum C-reactive protein concentrations were determined by a high sensitivity immunoradiometric assay. C-reactive protein concentration was increased in association with the 1985 air pollution episode. In multivariate analyses, elevated concentrations were independently associated with concentrations of total suspended particles and the sulphur dioxide episode. At ambient concentrations of pollution, as noted during the 1985 air pollution episode, the odds of observing C-reactive protein concentrations above 5.7 mg. l(-1)(>90th percentile) tripled, and increases of 26 microg. m(-3)total suspended particles (mean of 5 days) raised the odds of C-reactive protein levels 50% above the 90th percentile. CONCLUSIONS: Exposure to current levels of particulate matter in the atmosphere elicits an acute phase response in randomly selected healthy middle-aged men, which may contribute to the increased cardiovascular risk caused by air pollution.

Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein.

BACKGROUND: Reactive systemic (AA, secondary) amyloidosis occurs in chronic inflammatory diseases, and most patients present with nephropathy. The amyloid fibrils are derived from the circulating acute-phase reactant serum amyloid A protein (SAA), but the relation between production of fibril precursor protein, amyloid load, and clinical outcome in AA and other types of amyloidosis is unclear. METHODS: We studied amyloidotic organ function and survival prospectively for 12-117 months in 80 patients with systemic AA amyloidosis in whom serum SAA concentration was measured monthly and visceral amyloid deposits were assessed annually by serum amyloid P component scintigraphy. Underlying inflammatory diseases were treated as vigorously as possible. FINDINGS: Amyloid deposits regressed in 25 of 42 patients whose median SAA values were within the reference range (<10 mg/L) throughout follow-up, and amyloidotic organ function stabilised or improved in 39 of these cases. Outcome varied substantially among patients whose median SAA concentration exceeded 10 mg/L, but amyloid load increased and organ function deteriorated in most of those whose SAA was persistently above 50 mg/L. Estimated survival at 10 years was 90% in patients whose median SAA was under 10 mg/L, and 40% among those whose median SAA exceeded this value (p=0.0009). INTERPRETATION: Although isolated amyloid fibrils are stable in vitro, AA amyloid deposits exist in a state of dynamic turnover, and outcome is favourable in AA amyloidosis when the SAA concentration is maintained below 10 mg/L. The potential for amyloid to regress and for the function of amyloidotic organs to recover support therapeutic strategies to decrease the supply of amyloid fibril precursor proteins in amyloidosis generally.

C-reactive protein, insulin resistance, central obesity, and coronary heart disease risk in Indian Asians from the United Kingdom compared with European whites.

BACKGROUND: Indian Asians in the United Kingdom have increased coronary heart disease (CHD) mortality compared with European whites, but the causes are not well understood. Increased circulating concentrations of C-reactive protein (CRP) are an independent risk factor for CHD. Therefore, we investigated this marker of inflammation in healthy UK Indian Asian and European white men. Methods and Results-- We measured serum CRP concentrations and conventional CHD risk factors in 1025 healthy male subjects (518 Indian Asians and 507 European whites) aged 35 to 60 years who were recruited at random from general practitioner lists. The geometric mean CRP concentration was 17% higher (95% confidence interval, 3% to 33%) in Indian Asians compared with European whites. CRP values were strongly associated with conventional CHD risk factors, measures of obesity, and metabolic disturbances associated with insulin resistance in both racial groups. The difference in CRP concentrations between Indian Asians and European whites remained after adjustment for conventional CHD risk factors but was eliminated by an adjustment for central obesity and insulin resistance score in Asians. On the basis of these results, we estimate that the processes underlying elevated CRP and/or increased CRP production itself are associated with an approximately 14% increase in population CHD risk among Indian Asians compared with European whites. CONCLUSIONS: CRP concentrations are higher in healthy Indian Asians than in European whites and are accounted for by greater central obesity and insulin resistance in Indian Asians. Our results suggest that inflammation or other mechanisms underlying elevated CRP values may contribute to the increased CHD risk among Indian Asians.

Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie.

Following peripheral exposure to transmissible spongiform encephalopathies (TSEs), infectivity usually accumulates in lymphoid tissues before neuroinvasion. The host prion protein (PrPc) is critical for TSE agent replication and accumulates as an abnormal, detergent insoluble, relatively proteinase-resistant isoform (PrPSc) in diseased tissues. Early PrPSc accumulation takes place on follicular dendritic cells (FDCs) within germinal centers in lymphoid tissues of patients with variant Creutzfeldt-Jakob disease (vCJD), sheep with natural scrapie or rodents following experimental peripheral infection with scrapie. In mouse scrapie models, the absence of FDCs blocks scrapie replication and PrPSc accumulation in the spleen, and neuroinvasion is significantly impaired. The mechanisms by which the TSE agent initially localizes to lymphoid follicles and interacts with FDCs are unknown. Antigens are trapped and retained on the surface of FDCs through interactions between complement and cellular complement receptors. Here we show that in mice, both temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays the onset of disease following peripheral infection, and reduces the early accumulation of PrPSc in the spleen. Thus, in the early stages of infection, C3 and perhaps C1q contribute to the localization of TSE infectivity in lymphoid tissue and may be therapeutic targets.

C-reactive protein and atherothrombosis.

Circulating concentrations of C-reactive protein (CRP), the classical acute phase protein and sensitive systemic marker of inflammation, significantly predict atherothrombotic events and outcome after acute myocardial infarction, demonstrating the key role of inflammation in atherosclerosis and its complications. The binding specificity of CRP for low density lipoproteins, for modified low density lipoproteins, and for damaged and dead cells, coupled with the capacity of bound CRP to activate complement, and with the presence of CRP in atheroma and acute myocardial infarction lesions, all suggest a possible pathogenetic role of CRP. Development of drugs to block binding of CRP to its various ligands in vivo will enable this hypothesis to be tested.

Pathogenesis, diagnosis and treatment of systemic amyloidosis.

Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, insoluble fibrils that disrupt tissue structure and cause disease. Although about 20 different unrelated proteins can form amyloid fibrils in vivo, all such fibrils share a common cross-beta core structure. Some natural wild-type proteins are inherently amyloidogenic, form fibrils and cause amyloidosis in old age or if present for long periods at abnormally high concentration. Other amyloidogenic proteins are acquired or inherited variants, containing amino-acid substitutions that render them unstable so that they populate partly unfolded states under physiological conditions, and these intermediates then aggregate in the stable amyloid fold. In addition to the fibrils, amyloid deposits always contain the non-fibrillar pentraxin plasma protein, serum amyloid P component (SAP), because it undergoes specific calcium-dependent binding to amyloid fibrils. SAP contributes to amyloidogenesis, probably by stabilizing amyloid fibrils and retarding their clearance. Radiolabelled SAP is an extremely useful, safe, specific, non-invasive, quantitative tracer for scintigraphic imaging of systemic amyloid deposits. Its use has demonstrated that elimination of the supply of amyloid fibril precursor proteins leads to regression of amyloid deposits with clinical benefit. Current treatment of amyloidosis comprises careful maintenance of impaired organ function, replacement of end-stage organ failure by dialysis or transplantation, and vigorous efforts to control underlying conditions responsible for production of fibril precursors. New approaches under development include drugs for stabilization of the native fold of precursor proteins, inhibition of fibrillogenesis, reversion of the amyloid to the native fold, and dissociation of SAP to accelerate amyloid fibril clearance in vivo.

Effect of alcohol consumption on systemic markers of inflammation.

BACKGROUND: Epidemiological studies suggest that light to moderate alcohol intake is associated with lower all-cause mortality than abstention or heavy alcohol intake, primarily through reduced risk of coronary heart disease. The underlying mechanisms are incompletely understood. METHODS: We investigated the association between alcohol consumption (assessed by a 7-day food record) and concentrations of C-reactive protein (CRP), alpha1-globulins, alpha2-globulins, albumin, and transferrin, and leucocyte count in a sample of 2006 men and women aged 18-88 years participating in a national health survey carried out in former West Germany in 1987-88. Analyses were based on 781 men and 995 women with complete data. FINDINGS: Among men, alcohol consumption showed a U-shaped association with mean values of CRP (p for linear term 0.65, for quadratic term 0.048), alpha1-globulins (p=0.20, 0.0006), alpha2-globulins (p=0.82, 0.31), and leucocyte count (p=0.51, 0.26) even after adjustment for age, smoking, body-mass index, HDL and LDL cholesterol, history of hypertension, education, and income. There were inverted U-shaped associations between the negative acute-phase reactants albumin (p=0.41, 0.006) and transferrin (p=0.14, 0.28) and alcohol intake. In women, the associations were less strong for CRP (p=0.35, 0.31), leucocyte count (p=0.28, 0.15), and transferrin (p=0.86, 0.83). Concentrations of alpha1-globulins and alpha2-globulins were inversely related to alcohol consumption, and albumin showed a positive association with increasing alcohol intake in women. INTERPRETATION: Non-drinkers and heavy drinkers had higher CRP concentrations than moderate drinkers. In view of the robust association between markers of inflammation, especially CRP, and risk of coronary heart disease, an anti-inflammatory action of alcohol could contribute to the link between moderate consumption and lower cardiovascular mortality.

C-reactive protein and its role in the pathogenesis of myocardial infarction.

C-reactive protein (CRP), the classical acute phase reactant, has for some time contributed to both the diagnosis and management of a wide range of infective and inflammatory conditions. More recently with the advent of high sensitivity assays, the hypothesis that atherosclerosis is an inflammatory disease has been strengthened. "Elevated" CRP values predict a poor outcome for patients suffering from unstable coronary syndromes as well myocardial infarction, and large epidemiological surveys have shown that baseline values of CRP can predict future cardiovascular events in those at risk, as well as those otherwise well. Increasingly a direct role for CRP in the pathogenesis of atherosclerosis and post-myocardial infarction inflammation has also been suggested, and CRP itself may prove to be a future therapeutic target in the treatment of atherosclerosis and its consequences.

Association between C-reactive protein and features of the metabolic syndrome: a population-based study.

OBJECTIVE: To assess the association of circulating levels of C-reactive protein, a sensitive systemic marker of inflammation, with different components of the metabolic syndrome. RESEARCH DESIGN AND METHODS: Total cholesterol (TC), HDL cholesterol, triglycerides, uric acid, BMI , and prevalence of diabetes and hypertension were assessed in 747 men and 956 women aged 18-89 years who were participating in the population-based National Health and Nutrition Survey, which was carried out in former West Germany in 1987-1988. RESULTS: There was a statistically significant positive crude correlation between C-reactive protein and TC (R = 0.19), TG (R = 0.29), BMI (R = 0.32), glucose (R = 0.11), and uric acid (R = 0.14) (all P < 0.0001). A negative correlation was found between C-reactive protein and HDL cholesterol (R = 0.13, P < 0.0001). The age-adjusted geometric means of C-reactive protein concentrations in subjects grouped according to the presence of 0-1, 2-3, and > or =4 features of the metabolic syndrome were 1.11, 1.27, and 2.16 mg/l, respectively, with a statistically highly significant trend (P < 0.0001). CONCLUSIONS: The data suggest that a variety of features of the metabolic syndrome are associated with a systemic inflammatory response.

Role of serum amyloid P component in bacterial infection: protection of the host or protection of the pathogen.

Serum amyloid P component (SAP) binds to Streptococcus pyogenes, and we show here that it also binds to Neisseria meningitidis, including a lipopolysaccharide (LPS)-negative mutant, and to rough variants of Escherichia coli. Surprisingly, this binding had a powerful antiopsonic effect both in vitro and in vivo, reducing phagocytosis and killing of bacteria. Furthermore, SAP knockout mice survived lethal infection with S. pyogenes and rough E. coli J5, organisms to which SAP binds. The susceptibility of SAP(-/-) mice was fully restored by injection of isolated human SAP. However, SAP(-/-) mice were more susceptible than wild-type animals to lethal infection with E. coli O111:B4, a smooth strain to which SAP does not bind, suggesting that SAP also has some host defense function. Although SAP binds to LPS in vitro, SAP(-/-) mice were only marginally more susceptible to lethal LPS challenge, and injection of large amounts of human SAP into wild-type mice did not affect sensitivity to LPS, indicating that SAP is not a significant modulator of LPS toxicity in vivo. In contrast, the binding of SAP to pathogenic bacteria enabled them to evade neutrophil phagocytosis and display enhanced virulence. Abrogation of this molecular camouflage is thus potentially a novel therapeutic approach, and we show here that administration to wild-type mice of (R)-1-[6-(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine -2- carboxylic acid, a drug that inhibits SAP binding, significantly prolonged survival during lethal infection with E. coli J5.