Exploring potential mortality reductions in 9 European countries by improving diet and lifestyle: A modelling approach.

BACKGROUND: Coronary heart disease (CHD) death rates have fallen across most of Europe in recent decades. However, substantial risk factor reductions have not been achieved across all Europe. Our aim was to quantify the potential impact of future policy scenarios on diet and lifestyle on CHD mortality in 9 European countries. METHODS: We updated the previously validated IMPACT CHD models in 9 European countries and extended them to 2010-11 (the baseline year) to predict reductions in CHD mortality to 2020(ages 25-74years). We compared three scenarios: conservative, intermediate and optimistic on smoking prevalence (absolute decreases of 5%, 10% and 15%); saturated fat intake (1%, 2% and 3% absolute decreases in % energy intake, replaced by unsaturated fats); salt (relative decreases of 10%, 20% and 30%), and physical inactivity (absolute decreases of 5%, 10% and 15%). Probabilistic sensitivity analyses were conducted. RESULTS: Under the conservative, intermediate and optimistic scenarios, we estimated 10.8% (95% CI: 7.3-14.0), 20.7% (95% CI: 15.6-25.2) and 29.1% (95% CI: 22.6-35.0) fewer CHD deaths in 2020. For the optimistic scenario, 15% absolute reductions in smoking could decrease CHD deaths by 8.9%-11.6%, Salt intake relative reductions of 30% by approximately 5.9-8.9%; 3% reductions in saturated fat intake by 6.3-7.5%, and 15% absolute increases in physical activity by 3.7-5.3%. CONCLUSIONS: Modest and feasible policy-based reductions in cardiovascular risk factors (already been achieved in some other countries) could translate into substantial reductions in future CHD deaths across Europe. However, this would require the European Union to more effectively implement powerful evidence-based prevention policies.

Sex-specific trends in 4-year survival in 37 276 men and women with acute myocardial infarction before the age of 55 years in Sweden, 1987-2006: a register-based cohort study.

OBJECTIVE: To examine sex-specific trends in 4-year mortality among young patients with first acute myocardial infarction (AMI), 1987-2006. DESIGN: Prospective cohort study. SETTING: Sweden. PARTICIPANTS: We identified 37 276 cases (19.4% women; age, 25-54 years) from the Swedish Inpatient Register, 1987-2006, who had survived 28 days after an AMI. OUTCOME MEASURES: 4-year mortality from all causes and standard mortality ratio (SMR). RESULTS: From the first to last 5-year period, the absolute excess risk decreased from 1.38 to 0.50 and 1.53 to 0.59 per 100 person-years among men aged 25-44 and 45-54 years, respectively. Corresponding figures for women were a decrease from 2.26 to 1.17 and from 1.93 to 1.45 per 100 person-years, respectively. Trends for women were non-linear, decreasing to the same extent as those for men until the third period, then increasing. For the last 5-year period, the standardised mortality ratio for young survivors of AMI compared with the general population was 4.34 (95% CI 3.04 to 5.87) and 2.43 (95% CI 2.12 to 2.76) for men aged 25-44 and 45-54 years, respectively, and 13.53 (95% CI 8.36 to 19.93) and 6.42 (95% CI 5.24 to 7.73) for women, respectively. Deaths not associated with cardiovascular causes increased from 21.5% to 44.6% in men and 41.5% to 65.9% in women. CONCLUSIONS: Young male survivors of AMI have low absolute long-term mortality rates, but these rates remain twofold to fourfold that of the general population. After favourable development until 2001, women now have higher absolute mortality than men and a 6-fold to 14-fold risk of death compared with women in the general population.

The association between plasma homocysteine and coronary heart disease is modified by the MTHFR 677C>T polymorphism.

OBJECTIVE: An elevated level of total plasma homocysteine (tHcy) has been associated with risk of coronary heart disease (CHD). The level of tHcy is affected by lifestyle, in addition to genetic predisposition. The methylene tetrahydrofolate reductase (MTHFR) 677C>T polymorphism (rs1801133) is among the strongest genetic predictors of tHcy. We examined whether the association between tHcy and CHD is modified by the MTHFR 677C>T polymorphism. DESIGN AND SETTING: Data from two case-control studies of first-time myocardial infarction (MI), Stockholm Heart Epidemiology Programme (SHEEP), and for MI and unstable angina, INTERGENE, were analysed in parallel. PATIENTS: THcy was determined in a total of 1150 cases and 1753 controls. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The outcome comprised first-time MI and unstable angina, subsumed as CHD. Logistic regression was used to investigate the association between tHcy and CHD, and its modification by genotype. RESULTS: High tHcy was confirmed to be a risk factor for CHD in both studies. In SHEEP, the association between tHcy and MI was observed in MTHFR 677 C-homozygotes (OR=1.4, 95% CI 1.2 to 1.6, for a difference by 1 SD of log tHcy) and in heterozygotes (OR=1.3, 95% CI 1.1 to 1.6) but not in T-homozygotes, independent of smoking, physical activity and obesity. An effect modification of similar magnitude was observed but not statistically significant in the smaller INTERGENE study, and confirmed in a meta-analysis of both studies. CONCLUSIONS: Two Swedish case-control studies showed that the association between elevated tHcy and CHD was confined to carriers of the MTHFR 677 C-allele, which could have implications for the efficiency of tHcy-lowering treatment.

Perceived stress and incidence of Type 2 diabetes: a 35-year follow-up study of middle-aged Swedish men.

AIM: To explore incident cases of diagnosed diabetes over 35 years of follow-up in relation to self-perceived stress at baseline. METHODS: This was a population-based random sample of 7251 men derived from the Primary Prevention Trial Study, aged 47-56 years at baseline and without prior history of diabetes, coronary heart disease and stroke. Incident diabetes was identified from hospital discharge and death registries as principal or secondary diagnosis. Cox proportional hazards regression was used to evaluate the potential association between stress and diabetes. RESULTS: During a 35-year follow-up, a total of 899 men were identified with diabetes. The crude incidence was 5.2 per 1000 persons-years. At baseline, 15.5% men reported permanent stress related to conditions at work or home. After adjusting for age and competing risk of death, the estimated 35-year conditional probability of diabetes in men with permanent stress was 42.6%, compared with 31.0% for those with periodic stress and 31.2% with no stress. In age-adjusted Cox regression analysis, men with permanent stress had a higher risk of diabetes [hazard ratio 1.52 (95% CI 1.26-1.82)] compared with men with no (referent) or periodic stress [hazard ratio 1.09 (95% CI 0.94-1.27)]. The association between stress and diabetes was slightly attenuated but remained significant after adjustment for age, socio-economic status, physical inactivity, BMI, systolic blood pressure and use of anti-hypertensive medication [hazard ratio 1.45 (95% CI 1.20-1.75)]. When examining principal diagnosis of diabetes cases separately from secondary diagnoses cases, the excess risk of diabetes associated with permanent stress remained significant both in age (only) and multivariable adjusted models. CONCLUSION: Self-perceived permanent stress is an important long-term predictor of diagnosed diabetes, independently of socio-economic status, BMI and other conventional Type 2 diabetes risk factors.

Gender differences in the prevalence of metabolic syndrome in 50-year-old Swedish men and women with hypertension born in 1953.

To investigate potential gender differences in the role of hypertension as a risk factor for metabolic syndrome (MetS) we used a random population sample of 50-year-old men (n=595) and women (n=667; all born in 1953) who were examined in 2003-2004. Systolic (SBP) and diastolic (DBP) blood pressure values were dichotomized at ≥ 140 mm Hg and ≥ 90 mm Hg, respectively. MetS was defined using NCEP (National Cholesterol Education Programme) and IDF (International Diabetes Federation) criteria. MetS was more prevalent in men than in women (NCEP 16% versus 10%, P=0.003; IDF 26% versus 16%, P=0.000) and systolic hypertension was more common in men than in women (high SBP 24% versus 18%, P=0.003; high DBP 29% versus 24%, P=0.074). Women with high SBP had about a seven-fold increased NCEP risk compared with normotensive women (odds ratio (OR) 6.91, confidence interval (CI) 2.90-16.42), whereas high SBP in men was associated with about a three-fold increased NCEP risk (OR 2.72, CI 1.69-4.38). A similar pattern was observed for the IDF criterion of MetS. All interaction terms (sex × hypertension) were significant at P<0.01. At middle age, despite that fewer women had hypertension or MetS than men, hypertension carries a relatively greater risk for MetS in women than in men.

Increasing evidence-based treatments to reduce coronary heart disease mortality in Sweden: quantifying the potential gains.

OBJECTIVES: Between 1986 and 2002, coronary heart disease (CHD) mortality in Sweden fell by more than 50%. Approximately one-third (4800 fewer deaths) of this decline in age-adjusted CHD mortality could be attributed to treatments in patients with CHD and primary prevention medications. High treatment levels were achieved in some cases, but in others, only 50-80% of eligible patients received appropriate therapy. We therefore examined to what extent increasing the use of specific treatments in eligible patients might have reduced CHD mortality rates in Sweden. DESIGN AND METHODS: We used the previously validated IMPACT CHD model to combine data on CHD patient numbers, medical and surgical uptake levels and treatment effectiveness. We estimated the number of deaths prevented or postponed for 2002 (baseline scenario) and for an alternative scenario (if at least 60% of eligible patients were treated). RESULTS: If treatments were increased to consistently cover at least 60% of eligible patients, approximately 8900 deaths could have been postponed or prevented, representing a potential gain of approximately 4100 fewer deaths than actually occurred in 2002. Approximately 45% of the 4100 gain would have come from primary prevention with statins, 23% from acute coronary syndrome treatments, 15% from secondary prevention therapies and 15% from treatments for heart failure. CONCLUSION: Increasing the proportion of eligible patients with CHD who receive evidence-based treatment could have resulted in approximately 4100 fewer deaths in 2002, almost doubling the actual mortality reduction. These findings further emphasize the importance of aggressively identifying and treating patients with CHD and high-risk individuals.

Smoking in relation to ST-segment elevation acute myocardial infarction: findings from the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions.

OBJECTIVES: In the past few decades, clinical presentation in AMI has been reported to be changing, with milder cases and less ST-elevation myocardial infarction, the most serious form of AMI. The better outcome may be due to improved medical and interventional management, as well as more sensitive methods for detecting AMI. However, changes in risk factors have also been documented, especially lower tobacco-smoking rates. Therefore, the relation between smoking and ST-elevation AMI in a large observational cohort was analysed. METHODS: Data were derived from 93 416 consecutive patients aged 25 to 84 years and admitted to hospital between 1996 and 2004 with a first AMI. RESULTS: Tobacco smoking was more prevalent in younger patients (ie, <65 years). More than 50% of younger patients presenting with STEMI were smokers at the time of hospitalisation. After multiple adjustments, smoking was found to be an independent determinant for presenting with STEMI compared with non-STEMI. The adjusted odds ratio (OR) associated with smoking was 2.01 (99% CI 1.75 to 2.30) in younger women and 1.33 (99% CI 1.22 to 1.43) in younger men, with a significant interaction between smoking and gender. In older women and men (> or =65 years), the corresponding ORs were 1.33 (99% CI 1.20 to 1.48) and 1.14 (99% CI 1.04 to 1.25), respectively. CONCLUSION: Tobacco smoking is a major determinant for presenting with STEMI compared with non-STEMI, particularly among younger patients and among women. These results indicate that smoking is one of the major risk factors for presenting with more severe AMIs.

Immune-response against Streptococcus pyogenes in the development of abdominal aortic aneurysm--a population-based case-control study.

BACKGROUND: In a population-based case-control study the association between antibodies to Streptococcus pyogenes antigens and the development of abdominal aortic aneurysm (AAA) was analysed. PATIENTS AND METHODS: Forty-two patients with screening-detected AAA were compared to 100 age- and sex matched controls with normal aortas. Antibodies against three recently characterized cell wall-attached proteins of S. pyogenes (SclA, SclB and GRAB) were analysed in plasma samples obtained at screening (current), and in samples obtained from a study conducted 12 years previously on the same population (historical). RESULTS: Historical antibody levels against the S. pyogenes antigen GRAB were significantly higher in AAA patients compared with controls (0.25 vs 0.17, p = 0.021). A similar trend was observed in current GRAB antibody levels (0.23 vs 0.17, p = 0.072). GRAB-antibody levels at age 60 years retained the association with AAA in a logistic regression model after adjustment for a history of atherosclerosis (OR 20.2, p = 0.022), current smoking (OR 21.4, p = 0.025) and family history of AAA (OR 12.9, p = 0.053). Current and historical antibody levels against SclA and SclB in AAA patients were similar to those in controls. CONCLUSIONS: The results indicate that the immune response against S. pyogenes protein GRAB may be involved in the pathogenesis of AAA.

Interactions between surface proteins of Streptococcus pyogenes and coagulation factors modulate clotting of human plasma.

Invasive and toxic infections caused by Streptococcus pyogenes are connected with high morbidity and mortality. Typical symptoms of these infections are hypotension, edema formation, tissue necrosis, and bleeding disorders. Here we report that components of the coagulation system including fibrinogen, factors V, XI, and XII, and H-kininogen, are assembled at the surface of S. pyogenes through specific interactions with bacterial surface proteins. In plasma environment, absorption of fibrinogen by S. pyogenes causes a hypocoagulatory state resulting in prolonged clotting times and impaired fibrin network formation. Moreover, the binding of coagulation factors and the subsequent activation of the coagulation system at the bacterial surface lead to the formation of a fibrin network covering S. pyogenes bacteria adhering to epithelial cells. The results suggest that interactions between S. pyogenes and components of the coagulation system contribute to some of the symptoms seen in severe infections caused by this important human pathogen.

Bovine anti-Helicobacter pylori antibodies for oral immunotherapy.

BACKGROUND: Passive immunization with orally administered antibodies against specific pathogens has previously been successfully used therapeutically in both animal and human studies. We employed a similar strategy for experimental treatment of mice infected with the gastric pathogen Helicobacter pylori. METHODS: An anti-H. pylori bovine colostral hyperimmune immunoglobulin preparation (BIC) was generated and its efficacy was tested in different in vitro experiments, such as binding to the Lewis(b) blood group antigen, inhibition of adherence of H. pylori to human gastric mucosa tissue sections in situ and in a haemagglutination assay. The BIC preparation was also given in the drinking water to H. pylori-infected mice. RESULTS: An inhibition of 95% of the binding of H. pylori to Lewis(b) glycoconjugate was observed in vitro. Furthermore, a blocking activity of almost 90% was observed when the BIC was preincubated with H. pylori bacteria. Finally, the BIC preparation inhibited the haemagglutination of H. pylori and human red blood cells. Seven of 40 (17.5%) mice remained infected in the treatment group as compared with 25 of 45 (55.5%) in the control group. Hence, the cure rate was 66%, P = < 0.001. The mean number of colonies in the antibody-treated mice where eradication was not successful was also reduced (P < 0.05). In trials using FVB/N transgenic Lewis(b) expressing mice, a cure rate of 50%-66% was observed. CONCLUSION: Bovine colostral antibodies against H. pylori can be generated in high titres, inhibit binding in vitro and can eradicate or reduce the number of bacteria in infected mice.

Unique regulation of SclB - a novel collagen-like surface protein of Streptococcus pyogenes.

Slipped-strand mispairing at sites containing so-called coding repeats (CRs) can lead to phase variation of surface proteins in Gram-negative bacteria. This mechanism, believed to contribute to virulence, has so far not been identified in a Gram-positive bacterium. In the genome of the Gram-positive human pathogen Streptococcus pyogenes, we identified pentanucleotide CRs within a putative signal sequence of an open reading frame (ORF) encoding a novel collagen-like surface protein, denoted SclB. In 12 S. pyogenes strains, the number of CRs in the sclB gene varied from three to 19, rendering the start codon in frame with the downstream ORF in four strains and out of frame in eight strains. A protein reacting with anti-SclB antibodies could only be solubilized from three strains, all containing an intact sclB gene. Variations in the number of CRs were observed within strains of the same M serotype and occurred during growth of S. pyogenes in fresh human blood, but not in medium. The SclB protein has a hypervariable N-terminal part, a collagen-like central part and a typical cell wall sorting sequence containing the LPXTGX motif. SclB is related to the collagen-like SclA and is, like SclA, involved in the adhesion of S. pyogenes bacteria to human cells. However, the Mga protein, known to upregulate sclA and several additional genes encoding virulence factors of S. pyogenes, downregulates sclB transcription. This observation and the potential of SclB to phase vary by slipped-strand mispairing emphasize the unique regulation of this novel S. pyogenes surface protein.

Staphylococcus aureus induces release of bradykinin in human plasma.

Staphylococcus aureus is a prominent human pathogen. Here we report that intact S. aureus bacteria activate the contact system in human plasma in vitro, resulting in a massive release of the potent proinflammatory and vasoactive peptide bradykinin. In contrast, no such effect was recorded with Streptococcus pneumoniae. In the activation of the contact system, blood coagulation factor XII and plasma kallikrein play central roles, and a specific inhibitor of these serine proteinases inhibited the release of bradykinin by S. aureus in human plasma. Furthermore, fragments of the cofactor H-kininogen of the contact system efficiently blocked bradykinin release. The results suggest that activation of the contact system at the surface of S. aureus and the subsequent release of bradykinin could contribute to the hypovolemic hypotension seen in patients with severe S. aureus sepsis. The data also suggest that the contact system could be used as a target in the treatment of S. aureus infections.

Immunoglobulin-binding domains of peptostreptococcal protein L enhance vaginal colonization of mice by Streptococcus gordonii.

Protein L, an immunoglobulin-binding protein of some strains of the anaerobic bacterium Peptostreptococcus magnus, has been hypothesized to be a virulence determinant in bacterial vaginosis. In order to investigate the role of protein L in peptostreptococcal virulence, the Ig-binding domains of protein L were expressed at the surface of the human oral commensal Streptococcus gordonii. Recombinant streptococci were used in vaginal colonization experiments, and protein L-expressing S. gordonii demonstrated enhanced ability to colonize the vaginal mucosa. Compared to the control strain, they also persisted for a longer period in the murine vagina.

Dermatan sulphate is released by proteinases of common pathogenic bacteria and inactivates antibacterial alpha-defensin.

Defensins represent an evolutionarily conserved group of small peptides with potent antibacterial activities. We report here that extracellular proteinases secreted by the human pathogens Pseudomonas aeruginosa, Enterococcus faecalis and Streptococcus pyogenes release dermatan sulphate by degrading dermatan sulphate-containing proteoglycans, such as decorin. Dermatan sulphate was found to bind to neutrophil-derived alpha-defensin, and this binding completely neutralized its bactericidal activity. During infection, proteoglycan degradation and release of dermatan sulphate may therefore represent a previously unknown virulence mechanism, which could serve as a target for novel antibacterial strategies.

Severe lung lesions caused by Salmonella are prevented by inhibition of the contact system.

Vascular damage induced by trauma, inflammation, or infection results in an alteration of the endothelium from a nonactivated to a procoagulant, vasoconstrictive, and proinflammatory state, and can lead to life-threatening complications. Here we report that activation of the contact system by Salmonella leads to massive infiltration of red blood cells and fibrin deposition in the lungs of infected rats. These pulmonary lesions were prevented when the infected animals were treated with H-D-Pro-Phe-Arg-chloromethylketone, an inhibitor of coagulation factor XII and plasma kallikrein, suggesting that inhibition of contact system activation could be used therapeutically in severe infectious disease.

SclA, a novel collagen-like surface protein of Streptococcus pyogenes.

Surface proteins of Streptococcus pyogenes are important virulence factors. Here we describe a novel collagen-like surface protein, designated SclA (streptococcal collagen-like surface protein). The sclA gene was identified in silico using the Streptococcal Genome Sequencing Project with the recently identified protein GRAB as the probe. SclA has a signal sequence and a cell wall attachment region containing the prototypic LPXTGX motif. The surface-exposed part of SclA contains a unique NH(2)-terminal domain of 73 amino acids, followed by a collagen-like region. The sclA gene was found to be positively regulated by Mga, a transcriptional activator of several S. pyogenes virulence determinants. A mutant lacking cell wall-associated SclA was constructed and was found to be as effective as wild-type bacteria in platelet aggregation, survival in fresh human blood, and adherence to pharyngeal cells. The sclA gene was found in all 12 S. pyogenes strains that were investigated using PCR. Sequence analysis revealed that the signal sequence and the cell wall attachment region are highly conserved. The collagen-like domain is variable in its NH(2)-terminal region and has conserved repeated domains in its COOH-terminal part. SclA proteins from most strains have additional proline-rich repeats spacing the collagen-like domain and the cell wall attachment sequence. The unique NH(2)-terminal region is hypervariable, but computer predictions indicate a common secondary structure, with two alpha helices connected by a loop region. Immune selection may explain the hypervariability in the NH(2)-terminal region, whereas the preserved secondary structure implies that this region has a common function. These features and the Mga regulation are shared with the M protein of S. pyogenes. Moreover, as with the gene encoding the M protein, phylogenetic analysis indicates that horizontal gene transfer has contributed to the evolution of sclA.

Virulent aggregates of Streptococcus pyogenes are generated by homophilic protein-protein interactions.

Many strains of the important human pathogen Streptococcus pyogenes form aggregates when grown in vitro in liquid medium. The present studies demonstrate that this property is crucial for the adherence, the resistance to phagocytosis and the virulence of S. pyogenes. A conserved sequence of 19 amino acid residues (designated AHP) was identified in surface proteins of common S. pyogenes serotypes. This sequence was found to promote bacterial aggregation through homophilic protein-protein interactions between AHP-containing surface proteins of neighbouring bacteria. A synthetic AHP peptide inhibited S. pyogenes aggregation, reduced the survival of S. pyogenes in human blood and attenuated its virulence in mice. In contrast, mutant bacteria devoid of surface proteins containing AHP-related sequences did not aggregate or adhere to epithelial cells. These bacteria are also rapidly killed in human blood and show reduced virulence in mice, underlining the pathogenic significance of the AHP sequence and S. pyogenes aggregation.

Hic, a novel surface protein of Streptococcus pneumoniae that interferes with complement function.

The important human pathogen Streptococcus pneumoniae was found to absorb factor H, an inhibitor of complement, from human plasma. We identified the gene encoding a novel surface protein, factor H-binding inhibitor of complement (Hic), in the pspC locus of type 3 pneumococci. Unlike PspC proteins in other serotypes, Hic is anchored to the cell wall by means of an LPXTG motif, and the overall sequence homology to various PspC proteins is low. However, the NH(2)-terminal region showed significant homology to the NH(2)-terminal region of several PspC proteins. A fragment of Hic, covering this homologous region, was expressed as a glutathione S-transferase (GST) fusion protein. GST:Hic(39-261) bound radiolabeled factor H and inhibited binding of factor H to pneumococci of different serotypes. Interaction kinetics between GST:Hic(39-261) and factor H were studied with surface plasmon resonance and showed a high affinity binding (K(A) = 5 x 10(7), K(D) = 2.3 x 10(-)(8)). Mutant pneumococci lacking Hic showed no absorption of factor H in human plasma and no binding of radiolabeled factor H, suggesting that Hic is responsible for factor H-binding in type 3 pneumococci. Factor H-dependent inhibition of the alternative pathway was not diminished by the presence of GST:Hic(39-261). In addition, an intrinsic inhibitory effect of Hic is suggested.

Bacterial immunoglobulin superantigen proteins A and L activate human heart mast cells by interacting with immunoglobulin E.

Human heart mast cells (HHMC) have been identified in heart tissue, perivascularly, and in the intima of coronary arteries. In vitro activation of isolated HHMC induces the release of vasoactive and proinflammatory mediators (histamine, tryptase, and cysteinyl leukotriene C(4) [LTC(4)]). We investigated the effects of several bacterial proteins on HHMC activation in vitro. HHMC released histamine, tryptase, and LTC(4) in response to Staphylococcus aureus Cowan 1 and the immunoglobulin (Ig)-binding protein A, but not to S. aureus Wood 46, which does not synthesize protein A. The effect of protein A was inhibited by preincubation with monoclonal IgM V(H)3(+). Some strains of Peptostreptococcus magnus express an Ig light chain-binding surface protein called protein L. Such bacteria and soluble protein L stimulated the release of preformed and newly synthesized mediators from HHMC. Preincubation of HHMC with either protein A or protein L resulted in complete cross-desensitization to a subsequent challenge with the heterologous stimulus or anti-IgE. Monoclonal IgE (kappa chains) blocked protein L-induced release, whereas IgE (lambda chains) had no effect. Streptococcal protein G, formyl-containing tripeptide, and pepstatin A did not activate HHMC. Bacterial products protein A and protein L and intact bacteria (S. aureus and P. magnus) activate HHMC by acting as Ig superantigens.