Moïse Desvarieux

Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project) : a meta-analysis of individual participant data

BACKGROUND Carotid intima-media thickness (cIMT) is related to the risk of cardiovascular events in the general population. An association between changes in cIMT and cardiovascular risk is frequently assumed but has rarely been reported. Our aim was to test this association. METHODS We identified general population studies that assessed cIMT at least twice and followed up participants for myocardial infarction, stroke, or death. The study teams collaborated in an individual participant data meta-analysis. Excluding individuals with previous myocardial infarction or stroke, we assessed the association between cIMT progression and the risk of cardiovascular events (myocardial infarction, stroke, vascular death, or a combination of these) for each study with Cox regression. The log hazard ratios (HRs) per SD difference were pooled by random effects meta-analysis. FINDINGS Of 21 eligible studies, 16 with 36,984 participants were included. During a mean follow-up of 7·0 years, 1519 myocardial infarctions, 1339 strokes, and 2028 combined endpoints (myocardial infarction, stroke, vascular death) occurred. Yearly cIMT progression was derived from two ultrasound visits 2-7 years (median 4 years) apart. For mean common carotid artery intima-media thickness progression, the overall HR of the combined endpoint was 0·97 (95% CI 0·94-1·00) when adjusted for age, sex, and mean common carotid artery intima-media thickness, and 0·98 (0·95-1·01) when also adjusted for vascular risk factors. Although we detected no associations with cIMT progression in sensitivity analyses, the mean cIMT of the two ultrasound scans was positively and robustly associated with cardiovascular risk (HR for the combined endpoint 1·16, 95% CI 1·10-1·22, adjusted for age, sex, mean common carotid artery intima-media thickness progression, and vascular risk factors). In three studies including 3439 participants who had four ultrasound scans, cIMT progression did not correlate between occassions (reproducibility correlations between r=-0·06 and r=-0·02). INTERPRETATION The association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. No conclusion can be derived for the use of cIMT progression as a surrogate in clinical trials. FUNDING Deutsche Forschungsgemeinschaft.

Periodontal bacteria and hypertension: the oral infections and vascular disease epidemiology study (INVEST)

Objective Chronic infections, including periodontal infections, may predispose to cardiovascular disease. We investigated the relationship between periodontal microbiota and hypertension. Methods and results Six hundred and fifty-three dentate men and women with no history of stroke or myocardial infarction were enrolled in INVEST. We collected 4533 subgingival plaque samples (average of seven samples per participant). These were quantitatively assessed for 11 periodontal bacteria using DNA–DNA checkerboard hybridization. Cardiovascular risk factor measurements were obtained. Blood pressure and hypertension (SBP ≥140 mmHg, DBP ≥90 mmHg or taking antihypertensive medication, or self-reported history) were each regressed on the level of bacteria: considered causative of periodontal disease (etiologic bacterial burden); associated with periodontal disease (putative bacterial burden); and associated with periodontal health (health-associated bacterial burden). All analyses were adjusted for age, race/ethnicity, sex, education, BMI, smoking, diabetes, low-density lipoprotein and high-density lipoprotein cholesterol. Etiologic bacterial burden was positively associated with both blood pressure and prevalent hypertension. Comparing the highest and lowest tertiles of etiologic bacterial burden, SBP was 9 mmHg higher, DBP was 5 mmHg higher (P for linear trend was less than 0.001 in each case), and the odds ratio for prevalent hypertension was 3.05 (95% confidence interval 1.60–5.82) after multivariable adjustment. Conclusion Our data provide evidence of a direct relationship between the levels of subgingival periodontal bacteria and both SBP and DBP as well as hypertension prevalence.

Changes in Clinical and Microbiological Periodontal Profiles Relate to Progression of Carotid Intima‐Media Thickness: The Oral Infections and Vascular Disease Epidemiology Study

Background No prospective studies exist on the relationship between change in periodontal clinical and microbiological status and progression of carotid atherosclerosis. Methods and Results The Oral Infections and Vascular Disease Epidemiology Study examined 420 participants at baseline (68±8 years old) and follow‐up. Over a 3‐year median follow‐up time, clinical probing depth (PD) measurements were made at 75 766 periodontal sites, and 5008 subgingival samples were collected from dentate participants (average of 7 samples/subject per visit over 2 visits) and quantitatively assessed for 11 known periodontal bacterial species by DNA‐DNA checkerboard hybridization. Common carotid artery intima‐medial thickness (CCA‐IMT) was measured using high‐resolution ultrasound. In 2 separate analyses, change in periodontal status (follow‐up to baseline), defined as (1) longitudinal change in the extent of sites with a ≥3‐mm probing depth (Δ%PD≥3) and (2) longitudinal change in the relative predominance of bacteria causative of periodontal disease over other bacteria in the subgingival plaque (Δetiologic dominance), was regressed on longitudinal CCA‐IMT progression adjusting for age, sex, race/ethnicity, diabetes, smoking status, education, body mass index, systolic blood pressure, and low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol. Mean (SE) CCA‐IMT increased during follow‐up by 0.139±0.008 mm. Longitudinal IMT progression attenuated with improvement in clinical or microbial periodontal status. Mean CCA‐IMT progression varied inversely across quartiles of longitudinal improvement in clinical periodontal status (Δ%PD≥3) by 0.18 (0.02), 0.16 (0.01), 0.14 (0.01), and 0.07 (0.01) mm (P for trend<0.0001). Likewise, mean CCA‐IMT increased by 0.20 (0.02), 0.18 (0.02), 0.15 (0.02), and 0.12 (0.02) mm (P<0.0001) across quartiles of longitudinal improvement in periodontal microbial status (Δetiologic dominance). Conclusion Longitudinal improvement in clinical and microbial periodontal status is related to a decreased rate of carotid artery IMT progression at 3‐year average follow‐up.

Gender Differences in the Relationship Between Periodontal Disease, Tooth Loss, and Atherosclerosis

Background and Purpose— Males carry a disproportionate burden of cardiovascular disease. Because males also bear a higher burden of periodontal disease, we investigated the existence of gender differences in the postulated relationship between periodontal infections, tooth loss, and subclinical atherosclerosis. Methods— A total of 1710 randomly enrolled participants between the ages of 45 and 75 with no history of myocardial infarction or stroke received a clinical periodontal examination, carotid scan using high-resolution B-mode ultrasound, and extensive measurements for conventional cardiovascular risk factors (age, education, smoking, alcohol, body mass index, diabetes, systolic blood pressure, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, and triglycerides) as well as markers of healthy lifestyle and social network. Results— In both genders, measures of current and long-term periodontitis worsened as tooth loss increased. In males but not females, an ≈10% difference in carotid artery plaque prevalence was observed between the lowest and highest tertiles of tooth loss (P <0.05) and long-term periodontitis (P =0.05) after multivariate adjustment. Similar patterns were observed for intima–media thickness. The influence of gender on carotid artery plaque prevalence was most evident among the younger age group (<59 years). Between genders, carotid plaque prevalence differed by 10%, 15%, and 25% across increasing levels of tooth loss, and by 5%, 15%, and 25% across increasing levels of long-term periodontitis. Conclusions— Our data suggest that tooth loss and long-term periodontitis are related to subclinical atherosclerosis in men but not women. Gender variations in cardiovascular morbidity or mortality may be explained partly by the differential contributions of novel risk factors across genders.

Effect of post-treatment isoniazid on prevention of recurrent tuberculosis in HIV-1-infected individuals: a randomised trial

BACKGROUND Patients with HIV-1 infection respond well to treatment for active tuberculosis, but whether such patients are at increased risk of disease recurrence after complete cure is uncertain. We did a randomised trial in Port au Prince, Haiti, to determine whether recurrent tuberculosis after curative tuberculosis treatment is more common in HIV-1-infected individuals than HIV-1-uninfected individuals, and to determine whether post-treatment isoniazid prophylaxis decreases the risk of recurrent tuberculosis. METHODS Patients older than 18 years who were diagnosed with a first episode of tuberculosis at the national HIV testing centre in Haiti, and who successfully completed a 6-month rifampicin-containing regimen for active pulmonary tuberculosis, were randomly assigned 1 year of post-treatment isoniazid prophylaxis or placebo. The primary outcome measure was rate of recurrent tuberculosis after at least 24 months. An intention-to-treat analysis was used. FINDINGS Of 354 patients with active pulmonary tuberculosis, 274 successfully completed treatment, and 233 were randomised. Of 142 HIV-1-positive patients, 68 were assigned isoniazid and 74 placebo. Of 91 HIV-1-negative individuals, 51 were assigned isoniazid and 40 placebo. The rate of recurrent tuberculosis was 4.8 per 100 person-years in HIV-1-infected individuals and 0.4 per 100 person-years in uninfected individuals (relative risk 10.7 [95% CI 1.4-81.6]). Among HIV-1-positive patients receiving isoniazid, the tuberculosis recurrence rate was 1.4 per 100 person-years, and among HIV-1-positive patients receiving placebo, it was 7.8 per 100 person-years (0.18 [0.04-0.83]). Among HIV-1-positive individuals, all cases of recurrent tuberculosis occurred in individuals with a history of HIV-1-related symptoms before initial tuberculosis diagnosis. INTERPRETATION The rate of recurrent tuberculosis is higher in HIV-1-positive individuals than in HIV-1-negative individuals, and is strongly associated with a history of symptomatic HIV-1 disease before initial tuberculosis diagnosis. Post-treatment isoniazid prophylaxis decreases the risk of recurrence in HIV-1-positive individuals, and should be considered for HIV-1-positive individuals with a history of HIV-1-related symptoms at the time of tuberculosis diagnosis.

Periodontal Status and A1C Change: Longitudinal results from the Study of Health in Pomerania (SHIP)

OBJECTIVE Infection may be a type 2 diabetes risk factor. Periodontal disease is a chronic infection. We hypothesized that periodontal disease was related to A1C progression in diabetes-free participants. RESEARCH DESIGN AND METHODS The Study of Health in Pomerania (SHIP) is a population-based cohort in Germany including 2,973 diabetes-free participants (53% women; aged 20–81 years). Participants were categorized into four groups according to increasing baseline periodontal disease levels (percentage of sites per mouth with attachment loss ≥5 mm, determined a priori); sample sizes for each respective category were 1,122, 488, 463, and 479 (241 participants were edentulous). Mean absolute changes (year 5 minus baseline) in A1C (ΔA1C) were regressed across periodontal categories while adjusting for confounders (e.g., age, sex, smoking, obesity, physical activity, and family history). RESULTS Across baseline periodontal disease categories, ΔA1C ± SEM values were 0.023 ± 0.02, 0.023 ± 0.02, 0.065 ± 0.03, and 0.106 ± 0.03 (Ptrend = 0.02), yielding an approximate fivefold increase in the absolute difference in ΔA1C when dentate participants in the highest versus lowest periodontal disease category were compared; these results were markedly stronger among participants with high-sensitivity C-reactive protein ≥1.0 mg/l (Pinteraction = 0.01). When individuals who had neither baseline periodontal disease nor deterioration in periodontal status at 5 years were compared with individuals with both poor baseline periodontal health and longitudinal periodontal deterioration, mean ΔA1C values were 0.005 vs. 0.143% (P = 0.003). CONCLUSIONS Periodontal disease was associated with 5-year A1C progression, which was similar to that observed for a 2-SD increase in either waist-to-hip ratio or age in this population.

Prevalence of periodontal disease and treatment demands based on a German dental survey (DMS IV)

AIM We assessed the prevalence and extent of periodontitis in Germany. Furthermore, region- and gender-specific differences in periodontal disease prevalence were evaluated. MATERIAL AND METHODS The fourth German Dental Health Survey is a national cross-sectional survey conducted in 2005. Nine hundred and twenty-five adults (35-44 years) and 1040 seniors (65-74 years) were examined. The survey comprised social- and health-related interviews and dental examinations. Probing depth (PD) and clinical attachment loss (CAL) were assessed at three sites at 12 index teeth. RESULTS Prevalence of CAL> or =3 mm was found in 95.0% in adults and 99.2% in seniors with 68.7% and 91.4% of teeth being affected, respectively. PD> or =4 mm was prevalent in 76.9% and 87.7% in both age groups, respectively. According to the CDC definition considering mesiobuccal and distolingual sites, prevalence of periodontitis was 70.9% and 87.4% in both age cohorts, with one-fourth and one-half presenting severe forms, respectively. Periodontal prevalence was significantly higher in male subjects and East German subjects. CONCLUSIONS Periodontitis was highly prevalent in German adults. To reduce periodontal burden, treatment of periodontal diseases and continuous maintenance should become an integral part in dental practice. Furthermore, health recommendations should be implemented at the community, professional, and individual level.

Periodontal microbiota and phospholipases: The Oral Infections and Vascular Disease Epidemiology Study (INVEST)

OBJECTIVE Periodontal infections have been linked to cardiovascular disease, including atherosclerosis, and systemic inflammation has been proposed as a possible mediator. Secretory phospholipase A2 (s-PLA2) and Lipoprotein-associated PLA2 (Lp-PLA2) are inflammatory enzymes associated with atherosclerosis. No data are available on the association between oral microbiota and PLA2s. We studied whether a relationship exists between periodontal microbiota and the activities of these enzymes. METHODS The Oral Infection and Vascular Disease Epidemiology Study (INVEST) collected subgingival biofilms and serum samples from 593 dentate men and women (age 68.7 ± 8.6 years). 4561 biofilm samples were collected in the two most posterior teeth of each quadrant (average 7/participant) for quantitative assessment of 11 bacterial species using DNA-DNA checkerboard hybridization. Mean concentration of s-PLA2 and activities of s-PLA2 and Lp-PLA2 were regressed on tertiles of etiologic dominance (ED). ED is defined as the level of presumed periodontopathic species/combined level of all eleven species measured, and represents the relative abundance of periodontopathic organisms. Analyses were adjusted for age, sex, race/ethnicity, education, smoking, BMI, diabetes, LDL cholesterol and HDL cholesterol, and systolic blood pressure. RESULTS Higher levels of s-PLA2 activity were observed across increasing tertiles of etiologic dominance (0.66 ± 0.04 nmol ml(-1) min(-1), 0.73 ± 0.04 nmol ml(-1) min(-1), 0.89 ± 0.04 nmol ml-1 min-1; p < 0.001), with also a trend of association between Lp-PLA2 activity and ED (p = 0.07), while s-PLA2 concentration was unrelated to ED. CONCLUSION Increasingly greater s-PLA2 activity at higher tertiles of etiologic dominance may provide a mechanistic explanatory link of the relationship between periodontal microbiota and vascular diseases. Additional studies investigating the role of s-PLA2 are needed.

Periodontal Status and Hemoglobin A1C Change: Longitudinal Results from the Study of Health in Pomerania (SHIP)

OBJECTIVE Infection may be a type 2 diabetes risk factor. Periodontal disease is a chronic infection. We hypothesized that periodontal disease was related to A1C progression in diabetes-free participants. RESEARCH DESIGN AND METHODS The Study of Health in Pomerania (SHIP) is a population-based cohort in Germany including 2,973 diabetes-free participants (53% women; aged 20–81 years). Participants were categorized into four groups according to increasing baseline periodontal disease levels (percentage of sites per mouth with attachment loss ≥5 mm, determined a priori); sample sizes for each respective category were 1,122, 488, 463, and 479 (241 participants were edentulous). Mean absolute changes (year 5 minus baseline) in A1C (ΔA1C) were regressed across periodontal categories while adjusting for confounders (e.g., age, sex, smoking, obesity, physical activity, and family history). RESULTS Across baseline periodontal disease categories, ΔA1C ± SEM values were 0.023 ± 0.02, 0.023 ± 0.02, 0.065 ± 0.03, and 0.106 ± 0.03 (Ptrend = 0.02), yielding an approximate fivefold increase in the absolute difference in ΔA1C when dentate participants in the highest versus lowest periodontal disease category were compared; these results were markedly stronger among participants with high-sensitivity C-reactive protein ≥1.0 mg/l (Pinteraction = 0.01). When individuals who had neither baseline periodontal disease nor deterioration in periodontal status at 5 years were compared with individuals with both poor baseline periodontal health and longitudinal periodontal deterioration, mean ΔA1C values were 0.005 vs. 0.143% (P = 0.003). CONCLUSIONS Periodontal disease was associated with 5-year A1C progression, which was similar to that observed for a 2-SD increase in either waist-to-hip ratio or age in this population.

Traditional Risk Factors Are Not Major Contributors to the Variance in Carotid Intima-Media Thickness

Background and Purpose— Carotid intima-media thickness (cIMT) was a widely accepted ultrasound marker of subclinical atherosclerosis in the past. Although traditional risk factors may explain ≈50% of the variance in plaque burden, they may not explain such a high proportion of the variance in IMT, especially when measured in plaque-freel ocations. We aimed this study to identify individuals with cIMT unexplained by traditional risk factors for future environmental and genetic research. Methods— As part of the Northern Manhattan Study, 1790 stroke-free individuals (mean age, 69±9 years; 60% women; 61% Hispanic; 19% black; 18% white) were assessed for cIMT using B-mode carotid ultrasound. Multiple linear regression models were evaluated: (1) incorporating prespecified traditional risk factors; and (2) including less traditional factors, such as inflammation biomarkers, adiponectin, homocysteine, and kidney function. Standardized cIMT residual scores were constructed to select individuals with unexplained cIMT. Results— Mean total cIMT was 0.92±0.09 mm. The traditional model explained 11% of the variance in cIMT. Age (7%), male sex (3%), glucose (<1%), pack-years of smoking (<1%), and low-density lipoprotein cholesterol (<1%) were significant contributing factors. The model, including inflammatory biomarkers, explained 16% of the variance in cIMT. Adiponectin was the only additional significant contributor to the variance in cIMT. We identified 358 individuals (20%) with cIMT unexplained by the investigated risk factors. Conclusions— Vascular risk factors explain only a small proportion of variance in cIMT. Identification of novel genetic and environmental factors underlying unexplained subclinical atherosclerosis is of utmost importance for future effective prevention of vascular disease.