Effect of causative genetic variants on atherosclerotic cardiovascular disease in heterozygous familial hypercholesterolemia patients.

Background: Heterozygous familial hypercholesterolemia (HFH) is an autosomal dominant genetic disorder leading to a lifetime exposure to high low-density lipoprotein cholesterol (LDL-c) level and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). We evaluate the effect of a causative genetic variant to predict ASCVD in HFH patients undergoing treatment. Materials and methods: A retrospective cohort was conducted on 289 patients with possible, probable, and definite diagnosis of HFH according to Dutch Lipid Clinic Network Score and in whom DNA analyses were performed and mean LDL-c level was above 155 mg/dl. The study population was divided into groups based on the presence or not of a causative variant (pathogenic or likely pathogenic). We observed each of the study's participants for the occurrence of ASCVD. Results: A causative variant was detected in 42.2% of study participants, and ASCVD has occurred in 21.5% of HFH patients. The incidence of ASCVD (27% vs. 17.4%, p = 0.048) and the mean of LDL-c under an optimal medical treatment (226 ± 59 mg/dl vs. 203 ± 37 mg/dl, p = 0.001) were higher in HFH-causative variant carriers than others. After adjusting on confounders, ASCVD was positively associated with LDL-c level [OR = 2.347; 95% (1.305-4.221), p = 0.004] and tends toward a negative association with HDL-c level [OR = 0.140; 95% (0.017-1.166), p = 0.059]. There is no more association between the detection of a causative variant and the occurrence of ASCVD [OR = 1.708; 95% (0.899-3.242), p = 0.102]. Kaplan Meier and log rank test showed no significant differences in event-free survival analysis between study groups (p = 0.523). Conclusion: In this study population under medical care, it seems that the presence of a causative variant did not represent an independent predictor of adverse cardiovascular outcomes in HFH patients, and LDL-c level played an undisputable causal role.

Real-World Efficacy of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors (PCSK9i) in Heterozygous Familial Hypercholesterolemia Patients Referred for Lipoprotein Apheresis.

BACKGROUND A small proportion of familial hypercholesterolemia (FH) patients can adequately control this condition, although achieving the recommended targets for low-density lipoprotein cholesterol (LDL-c) levels remains a challenge. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are new and potent lipid-lowering drugs. However, there is scarce literature on real-world data about their use in patients with FH. MATERIAL AND METHODS We examined the reduction in LDL-c levels from the baseline, after PCSK9i initiation in heterozygous familial hypercholesterolemia patients referred for lipoprotein apheresis in our regional lipid clinic. The study was conducted from March 2018 to September 2019, the period immediately after PCSK9i reimbursement was available in France. PCSK9i was added on top of the patients' maximal tolerated lipid-lowering regimens. RESULTS The study had 123 patients with heterozygous FH. The mean age of the patients was 59±11 years. The mean baseline LDL-c for all the participants was 277±78 mg/dl. It was 283±81 mg/dl in the PCSK9i monotherapy group (n=83), 247±68 mg/dl in the PCSK9i plus ezetimibe group (n=12), and 264±78 mg/dl in the PCSK9i plus statin and ezetimibe group (n=28). The mean decrease observed in the LDL-c level from baseline was 136±70 mg/dl (n=123), 125±60 mg/dl (n=83), 103±77 mg/dl (n=12), and 175±70 mg/dl (n=28), respectively. CONCLUSIONS An overall reduction of 49.1% from the baseline LDL-c was observed in the heterozygous FH population after PCSK9i initiation in a real-world experience. The group treated with PCSK9i ezetimibe plus statin showed further reduction of their LDL-c levels with a better responder rate, achieving the target 50% reduction in LDL-c from the baseline.

Ineffective Subtilisin/Kexin Type 9 (PCSK9) Inhibitors Monotherapy in Dyslipidemia with Low-Density Lipoprotein Cholesterol (LDL-C) Receptor Abnormalities: A Report of 2 Cases.

BACKGROUND Real-life data on the efficacy of monotherapy with PCSK9 inhibitors are scarce. Most cohort studies have examined populations that are not severely dyslipidemic and are receiving combined therapy rather than monotherapy. CASE REPORT From a series of 167 alirocumab prescriptions, we present a case of complete nonresponse and one of low response to monotherapy with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in 2 patients with heterozygous familial hypercholesterolemia and abnormalities of the low-density lipoprotein cholesterol (LDL-C) receptor. In these cases, PCSK9 inhibitors were ineffective when used alone to reduce the LDL-C level, but the addition of statin led to a dramatic improvement. CONCLUSIONS As PCSK9 inhibitors become more commonly prescribed, more cases of nonresponse to PCSK9 inhibitors will be identified. Prospective studies are needed to investigate the efficacy of treatment with the monoclonal antibodies PCSK9 inhibitors in the context of LDL-C receptor abnormalities and to determine whether a genetic explanation exists for interindividual differences in response.

Long-term Prognostic Impact of Physical Activity in Patients With Stable Coronary Heart Disease.

Stable coronary heart disease (CHD) patients are advised to practice regular physical activity (PA). However, data on very long-term prognosis impact of regular exercise remain scarce. We aimed to evaluate the impact of physical activity level on mortality at long term in stable CHD patients. We analyzed 822 patients with stable CHD. They answered questionnaires on medical history, underwent a standardized clinical examination, and provided a fasting blood sample. PA was evaluated by the MOSPA questionnaire. Three tertiles of patients were individualized according to PA level: 0.0-9 Metabolic Equivalent of Task (METs) hour per week (n = 267); 10-39.9 METs hour per week (n = 279); and ≥40 METs hour per week (n = 276). After a median follow-up of 14.6 years, 324 patients had died. In a multivariate analysis adjusted for age, dyslipidemia, smoking status, diabetes, high blood pressure, waist circumference, left ventricular ejection fraction, Gensini score, heart rate, ankle-brachial index and duration of disease, physical activity was significantly and independently associated with all-cause mortality. Compared to the lowest PA tertile, both the median and the highest PA tertiles, were associated to a reduction of all-cause mortality risk with hazard ratios at 0.79 (95%confidence interval [0.61:1.03], P = 0.08) and 0.71 ([0.53:0.96], P = 0.025) respectively; P for trend = 0.02. Adjusted hazard ratios for an increase of 10 METs hour per week was 0.95 [0.92 to 0.98], (P <0.002). In conclusion, our study demonstrates an independent association between PA and long term vital prognosis with a 5% total mortality decrease for an increase of 10 METs hour per week.

Common p2y13 polymorphisms are associated with plasma inhibitory factor 1 and lipoprotein(a) concentrations, heart rate and body fat mass: The GENES study.

BACKGROUND: The P2Y13 purinergic receptor regulates hepatic high-density lipoprotein uptake and biliary sterol secretion; it acts downstream of the membrane ecto-F1-adenosine triphosphatase, which generates extracellular adenosine diphosphate that selectively activates P2Y13, resulting in high-density lipoprotein endocytosis. Previous studies have shown that the serum concentration of the F1-adenosine triphosphatase inhibitor inhibitory factor 1 is negatively associated with cardiovascular risk. AIM: To evaluate whether p2y13 genetic variants affect cardiovascular risk. METHODS: Direct sequencing of the p2y13 coding and flanking regions was performed in a subcohort of 168 men aged 45-74 years with stable coronary artery disease and 173 control subjects from the GENES study. The two most frequent mutations, rs3732757 and rs1466684, were genotyped in 767 patients with coronary artery disease and 789 control subjects, and their association with cardiovascular risk markers was analysed. RESULTS: Carriers of the rs3732757 261T and rs1466684 557G alleles represented 9% and 27.5% of the entire population, respectively. The allele frequencies were identical in patients with coronary artery disease and control subjects. The presence of 261T was associated with higher concentrations of plasma lipoprotein A-I and inhibitory factor 1, increased fat mass and a lower heart rate. Moreover, the proportion of patients with coronary artery disease with a pejorative systolic ankle-brachial index was lower in carriers of the 261T allele. In both populations, the 557G allele was associated with increased concentrations of lipoprotein(a), and an allele dose effect was observed. CONCLUSIONS: Two frequent p2y13 variants are associated with specific bioclinical markers of cardiovascular risk. Although neither one of these variants appears to be related to the development of atherosclerotic disease, they may modulate the risk of additional cardiovascular complications.

Genetic diagnosis of familial hypercholesterolemia is associated with a premature and high coronary heart disease risk.

BACKGROUND: Familial hypercholesterolemia (FH) is a common autosomal dominant disease associated with premature coronary heart disease (CHD). Studies tend to show that patients with FH associated with an identified mutation (mutation+ FH) are at higher risk than patients without an identified mutation (mutation- FH). We compared the clinical and biological profile and the risk of CHD in patients with mutation+ FH and mutation- FH. HYPOTHESIS: In addition to LDL-C, a pathogenic mutation predicts premature CHD in FH. METHODS: We successively included all patients with suspected FH (LDL-C > 190 mg/dL if age > 18 years; LDL-C > 160 mg/dL if age < 18 years) and compared patients with a pathogenic mutation with those without an identified pathogenic mutation. RESULTS: We studied 179 patients with mutation+ FH and 147 with mutation- FH. The mean age was 44 (± 18) years. The lipid profile was more atherogenic in those with mutation+ FH, who had higher LDL-C (254 ± 69 mg/dL vs 218 ± 35 mg/dL; P < 0.01) and lower HDL-C (53 ± 14 mg/dL vs 58 ± 17 mg/dL; P < 0.01). Despite the more atherogenic nonlipid cardiovascular profile of patients with mutation- FH, the age of CHD onset was earlier in patients with mutation+ FH (48 vs 56 years; P = 0.026). After multiple adjustment, the presence of a positive mutation was significantly associated with premature CHD (OR: 3.0, 95% CI: 1.38-6.55, P < 0.01). CONCLUSIONS: Patients with mutation+ FH have a more atherogenic lipid profile and a 3-fold higher risk of premature CHD, as well as earlier onset of CHD, than patients with mutation- FH.

Association between serum alkaline phosphatase and coronary artery calcification in a sample of primary cardiovascular prevention patients.

BACKGROUND AND AIMS: A high level of serum alkaline phosphatase (ALP) is associated with an increased risk of mortality and myocardial infarction. ALP hydrolyses inorganic pyrophosphate, which is a strong inhibitor of calcium phosphate deposition. The aim of this study was to determine whether ALP is associated with the coronary artery calcium score (CACS). METHODS: We examined the association of CACS, assessed by computed tomography scanning, and ALP, in 500 patients consecutively recruited, free of cardiovascular disease. The CACS were categorized into two groups: no calcification (CACS = 0) (n = 187) and with calcification (CACS>0) (n = 313). ALP activity was divided into three tertile groups: low ALP level (<55 IU/L), intermediate (55-66 IU/L) and high ALP level (>66 IU/L). RESULTS: The mean age was 60.9 ± 10.8 years, 49.6% of the patients were women. ALP ranged from 22 to 164 IU/L (mean 62.6 IU/L, SD 19.3). In univariate analysis, traditional cardiovascular risk factors, statin use (p = 0.001), and ALP (p = 0.001) were significantly associated with CACS. After adjusting for cardiovascular risk factors, only age (p = 0.001) and sex (p = 0.001) were independently associated with CACS. Compared to the tertile group with low levels of ALP, the intermediate tertile group [OR 2.11, 95% CI (1.12; 3.96), p = 0.02], as well as the high tertile group [OR 3.89, 95% CI (2.01; 7.54), p = 0.001)], was independently associated with CACS. CONCLUSIONS: In patients free of cardiovascular disease, high ALP levels are positively and independently associated with coronary artery calcification. The metabolic pathway of ALP and inorganic pyrophosphate could be a target for new therapies against vascular calcification.

Serum levels of mitochondrial inhibitory factor 1 are independently associated with long-term prognosis in coronary artery disease: the GENES Study.

BACKGROUND: Epidemiological and observational studies have established that high-density lipoprotein cholesterol (HDL-C) is an independent negative cardiovascular risk factor. However, simple measurement of HDL-C levels is no longer sufficient for cardiovascular risk assessment. Therefore, there is a critical need for novel non-invasive biomarkers that would display prognostic superiority over HDL-C. Cell surface ecto-F1-ATPase contributes to several athero-protective properties of HDL, including reverse cholesterol transport and vascular endothelial protection. Serum inhibitory factor 1 (IF1), an endogenous inhibitor of ecto-F1-ATPase, is an independent determinant of HDL-C associated with low risk of coronary artery disease (CAD). This work aimed to examine the predictive value of serum IF1 for long-term mortality in CAD patients. Its informative value was compared to that of HDL-C. METHOD: Serum IF1 levels were measured in 577 male participants with stable CAD (age 45-74 years) from the GENES (Genetique et ENvironnement en Europe du Sud) study. Vital status was yearly assessed, with a median follow-up of 11 years and a 29.5 % mortality rate. Cardiovascular mortality accounted for the majority (62.4 %) of deaths. RESULTS: IF1 levels were positively correlated with HDL-C (r s = 0.40; P < 0.001) and negatively with triglycerides (r s = -0.21, P < 0.001) and CAD severity documented by the Gensini score (r s = -0.13; P < 0.01). Total and cardiovascular mortality were lower at the highest quartiles of IF1 (HR = 0.55; 95 % CI, 0.38-0.89 and 0.50 (0.28-0.89), respectively) but not according to HDL-C. Inverse associations of IF1 with mortality remained significant, after multivariate adjustments for classical cardiovascular risk factors (age, smoking, physical activity, waist circumference, HDL-C, dyslipidemia, hypertension, and diabetes) and for powerful biological and clinical variables of prognosis, including heart rate, ankle-brachial index and biomarkers of cardiac diseases. The 10-year mortality was 28.5 % in patients with low IF1 (<0.42 mg/L) and 21.4 % in those with high IF1 (≥0.42 mg/L, P < 0.02). CONCLUSIONS: We investigated for the first time the relation between IF1 levels and long-term prognosis in CAD patients, and found an independent negative association. IF1 measurement might be used as a novel HDL-related biomarker to better stratify risk in populations at high risk or in the setting of pharmacotherapy.

Ignorance of cardiovascular preventive measures is associated with all-cause and cardiovascular mortality in the French general population.

BACKGROUND: Cardiovascular disease (CVD) is the primary cause of premature death in Western countries. AIM: To assess the effect of patient ignorance of CVD risk modifiers on mortality. METHODS: We studied 4930 men and women in primary prevention, who consulted at the Department of Preventive Cardiology of a university hospital in France from 1995 to 2011. Questionnaires on socioeconomic level, medical history, cardiovascular risk factors, knowledge of CVD, drug intake, lifestyle and dietary recommendations, and adherence to treatments were administered by trained medical staff. Vital status (cause and date of death, in patients who died) was obtained through the French National Database. Multivariable predictive relationships with total mortality were evaluated using the Cox proportional hazards model. RESULTS: Mean follow-up was 8.6 years; 123 deaths, including 31 cardiovascular deaths, were recorded. Overall, 1305 patients (26%) were ignorant of CVD preventive measures; their mean age (53 years) was similar to that of the non-ignorant population, but most were men with a low educational level, a higher body mass index and significantly more cardiovascular risk factors (diabetes, hypertension). The ignorant group's lifestyle did not conform to cardiovascular guidelines, with less physical activity and more frequent inappropriate diet and smoking. All-cause and cardiovascular mortalities were higher among these patients. In the multivariable analysis, after adjusting for age, sex, smoking status, diabetes, hypertension, body mass index and educational status, ignorance of CVD preventive measures remained significantly associated with all-cause mortality (hazard ratio 1.93, 95% confidence interval 1.31-2.83; P<0.01). CONCLUSION: Ignorance of cardiovascular risk modifiers was significantly associated with all-cause mortality in a general French population.

Dutch Lipid Clinic Network low-density lipoprotein cholesterol criteria are associated with long-term mortality in the general population.

BACKGROUND: Heterozygous familial hypercholesterolaemia (HeFH) is a severe autosomal dominant disease that is underdiagnosed, inadequately treated and has a severe long-term cardiovascular risk. Few studies have evaluated the long-term risk of high low-density lipoprotein cholesterol (LDL-C) concentrations. AIM: To evaluate long-term mortality in a large cohort of healthy subjects, according to LDL-C concentrations. METHODS: Based on a sample of 6956 subjects visiting a preventive cardiology department, we selected adult subjects without a personal history of cardiovascular disease. From 1995 to 2011, 4930 healthy subjects were examined and followed up until 31 December 2011. All-cause deaths were collected exhaustively. A Cox-based multivariable analysis evaluated long-term total mortality risk according to Dutch Lipid Clinic Network (DLCN) LDL-C concentrations. RESULTS: After a mean follow-up of 8.6 years, 123 all-cause deaths were recorded (cumulative mortality rate, 2.5%). In the final multivariable model, major risk factors such as age, sex, tobacco use and diabetes were significantly associated with mortality. After adjustment for age, sex, tobacco use, hypertension, diabetes and statin therapy, and in comparison with subjects with LDL-C<4 mmol/L (<155 mg/dL), subjects with LDL-C between 4 and <5 mmol/L (155 to <190 mg/dL) had a hazard ratio (HR) of 1.99 (95% confidence interval [CI] 1.31-3.02; P=0.001), subjects with LDL-C between 5 and <6.5 mmol/L (190 to <250 mg/dL) had an HR of 1.81 (95% CI, 1.06-3.02; P=0.030), subjects with LDL-C between 6.5 and<8.5 mmol/L (250 to <330 mg/dL) had an HR of 2.69 (95% CI, 1.06-6.88; P=0.038) and subjects with LDL-C ≥ 8.5 mmol/L (≥330 mg/dL) had an HR of 6.27 (95% CI, 0.84-46.57; P=0.073). After excluding patients on statins at baseline, subjects with LDL-C ≥ 8.5 mmol/L (≥330 mg/dL) had an HR of 8.17 (95% CI, 1.08-62.73; P=0.042). CONCLUSIONS: The severity of LDL-C elevation is associated with a higher risk of death in healthy subjects. DLCN LDL-C concentrations may be used in daily practice to identify patients with HeFH who warrant aggressive treatment.

Association of hepatic lipase -514T allele with coronary artery disease and ankle-brachial index, dependence on the lipoprotein phenotype: the GENES study.

OBJECTIVES: Relationship between hepatic lipase (LIPC) polymorphism and coronary artery disease (CAD) has often led to contradictory results. We studied this relation by genotyping rs1800588 in the LIPC promoter in a case-control study on CAD (the GENES study). We also investigated the relationship between this polymorphism and the ankle-brachial index (ABI), which is predictive of atherosclerosis progression and complications in patients at high cardiovascular risk. METHODS: 557 men aged 45-74 with stable coronary artery disease and 560 paired controls were genotyped for rs1800588. Medical data, clinical examination including determination of ABI and biological measurements related to cardiovascular risk factors enabled multivariate analyses and multiple adjustments. RESULTS: CAD cases showed a higher T-allele frequency than controls (0.246 vs 0.192, p = 0.003). An interaction has been found between LIPC polymorphism and triglycerides (TG) levels regarding risk of CAD: TT-homozigosity was associated with an Odds ratio (OR) of 6.4 (CI: 1.8-22.3) when TG were below 1.5 g/L, but no association was found at higher TG levels (OR = 1.34, CI: 0.3-5.9). The distribution of LIPC genotypes was compared between CAD patients with normal or abnormal ABI and impact of LIPC polymorphism on ABI was determined. Following multiple adjustments, association of the T-allele with pejorative ABI (<0.90) was significant for heterozygotes and for all T-carriers (OR = 1.55, CI: 1.07-2.25). CONCLUSION: The -514T LIPC allele is associated with CAD under normotriglyceridemic conditions and constitutes an independent determinant of pejorative ABI in coronary patients.

Serum IF1 concentration is independently associated to HDL levels and to coronary heart disease: the GENES study.

HDL is strongly inversely related to cardiovascular risk. Hepatic HDL uptake is controlled by ecto-F1-ATPase activity, and potentially inhibited by mitochondrial inhibitor factor 1 (IF1). We recently found that IF1 is present in serum and correlates with HDL-cholesterol (HDL-C). Here, we have evaluated the relationship between circulating IF1 and plasma lipoproteins, and we determined whether IF1 concentration is associated with the risk of coronary heart disease (CHD). Serum IF1 was measured in 648 coronary patients ages 45-74 and in 669 matched male controls, in the context of a cross-sectional study on CHD. Cardiovascular risk factors were documented for each participant, including life-style habits and biological and clinical markers. In controls, multivariate analysis demonstrated that IF1 was independently positively associated with HDL-C and apoA-I (r = 0.27 and 0.28, respectively, P < 0.001) and negatively with triglycerides (r = -0.23, P < 0.001). Mean IF1 concentration was lower in CHD patients than in controls (0.43 mg/l and 0.53 mg/l, respectively, P < 0.001). In multivariate analyses, following adjustments on cardiovascular risk factors or markers, IF1 was negatively related to CHD (P < 0.001). This relationship was maintained after adjustment for HDL-C or apoA-I. This study identifies IF1 as a new determinant of HDL-C that is inversely associated with CHD.

Adiponectin and long-term mortality in coronary artery disease participants and controls.

OBJECTIVE: Despite cardioprotective properties, studies investigating adiponectin as a cardiovascular disease marker led to conflicting results. We investigated in participants with stable coronary artery disease (CAD) and controls whether serum adiponectin was associated with long-term mortality, considering varying degrees of CAD severity. METHODS AND RESULTS: A case-control design with prospective median follow-up of 8.1 years was used. Survival rates among 715 CAD men (aged 45-74 years) in increasing quartiles of serum adiponectin values were 87.5%, 85.6%, 76.4%, and 67.6%, respectively (P<0.001). Survival rates in 782 controls with adiponectin <9.1 µg/mL and ≥9.1 µg/mL (third quartile) were 95.3% and 91.0%, respectively (P=0.035). Adiponectin concentration above the highest quartile was associated with an increased risk of total and cardiovascular disease mortality in CAD patients (P=0.001 and P=0.001) and controls (P=0.02 and P=0.004). The associations among high adiponectin, total mortality, and cardiovascular disease mortality remained significant after multivariate adjustments for metabolic, cardiac, and CAD severity variables. No significant interaction was found among CAD patients, controls, and the relationship of adiponectin with mortality. CONCLUSIONS: High serum adiponectin is a predictor of mortality, particularly from cardiovascular disease. This prognostic value remains significant whatever the severity of the CAD and the metabolic status and is not different among people with and without CAD.

Prognostic usefulness of clinical and subclinical peripheral arterial disease in men with stable coronary heart disease.

The prognostic value of symptomatic peripheral arterial disease (PAD) in patients with coronary heart disease (CHD) is well documented, but few reports differentiating between symptomatic and asymptomatic forms of PAD are available. We investigated the respective prognostic effect of clinical and subclinical PAD on long-term all-cause mortality in patients with stable CHD. We analyzed 710 patients with stable CHD referred for hospitalization for CHD evaluation and management. As a part of the study, they completed questionnaires on medical history, underwent a standardized clinical examination, including ankle-brachial index (ABI) measurement, and provided a fasting blood sample. Three groups of patients were individualized: no PAD (no history of PAD and ABI >0.9 but ≤1.4); subclinical PAD (no history of PAD but abnormal ABI [i.e., ≤0.9 or >1.4); and clinical PAD (history of claudication, peripheral arterial surgery, or amputation due to PAD). Clinical and subclinical PAD was present in 83 (11.7%) and 181 (25.5%) patients, respectively. After a median follow-up of 7.2 years, 130 patients died. On multivariate analysis adjusted for age, hypertension, diabetes, dyslipidemia, smoking, left ventricular ejection fraction, CHD duration, heart rate, history of stroke or transient ischemic attack, and coronary revascularization, previous clinical PAD (hazard ratio 2.11, 95% confidence interval 1.28 to 3.47) and subclinical PAD (hazard ratio 1.65, 95% confidence interval 1.11 to 2.44) were significantly associated with increased all-cause mortality. In conclusion, our study has demonstrated that the detection of subclinical PAD by ABI in patients with stable CHD provides additional information for long-term mortality risk evaluation.

Arterial ultrasound screening as a tool for coronary risk assessment in asymptomatic men and women.

One of the imaging tests most commonly used to assess cardiovascular diseases (CVDs) in daily practice is Doppler ultrasonography of the carotid and femoral arteries. We included 2709 participants with no history or symptoms of CVD; they had a risk factor assessment and a carotid and femoral ultrasonography at baseline. Incident cases of definite coronary events were recorded during a median follow-up of 6 years. Approximately, 63% of the sample presented abnormalities (carotid stenosis >50%, carotid plaque, femoral plaque, increased intima-media thickness [IMT]). A moderately increased IMT (>0.63 mm) or the presence of carotid or femoral artery plaque was related to prognosis. The associations persisted after adjustment for pretest risk, treatment with statins, and other Doppler ultrasonography abnormalities. The hazard ratio increased significantly with the number of abnormalities (varying from 2.35 [1.16-4.74] to 14.83 [6.47-33.9]).

Undiagnosed airflow limitation in patients at cardiovascular risk.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD) share risk factors and impair each other's prognosis. AIMS: To assess the prevalence of airflow limitation (AL) compatible with COPD in a population at cardiovascular risk and to identify determinants of AL. METHODS: All consecutive patients referred to the cardiovascular prevention unit of a university hospital in 2009 were studied in a cross-sectional analysis. Patients answered questionnaires on socioeconomic status, medical history and lifestyle, and underwent extensive physical examinations, biological measures and spirometry testing. AL was defined as FEV1/FVC<0.70, without any history of asthma. Determinants of AL were assessed using logistic regression. RESULTS: The sample comprised 493 participants (mean age 57.4±11.1 years); 60% were men, 18% were current smokers, 42% were ex-smokers and 10% of patients had a history of CVD. Ten-year risk of coronary heart disease (CHD) according to the Framingham equation was intermediate (10-20%) for 25% of patients and high (>20%) for 10%. Prevalence of AL was 5.9% (95% confidence interval [CI] 4.0-8.3%) in the whole population and 4.3% (2.6-6.6%) among subjects in primary cardiovascular prevention. AL was independently associated with CVD (adjusted odds ratio 4.18, 95% CI 1.72-10.15; P=0.002) but not with Framingham CHD risk. More than 80% of patients screened with AL had not been diagnosed previously and more than one in two patients was asymptomatic. CONCLUSION: Patients with CVD are at increased risk of AL and thus should benefit from AL screening as they are frequently asymptomatic.

Prevalence of cardiovascular risk factors in men with stable coronary heart disease in France and Spain.

BACKGROUND: Cigarette smoking, raised blood pressure, unfavourable lipid concentrations, diabetes and - more indirectly - obesity, are responsible for most coronary heart disease events in developed and developing countries. AIMS: The objective of our study was to compare prevalence, treatment and control of cardiovascular risk factors in two samples of men with stable coronary heart disease, recruited in France and Spain. METHODS: Standardized measurements of body mass index, systolic and diastolic blood pressures, plasma lipids, glycaemia, and smoking were collected and drug use was registered. Cross-sectional comparisons were made between French and Spanish samples. RESULTS: Data from 982 individuals were analysed (420 French and 562 Spanish men). Current smoking was more frequent in Spain (p<0.001), whereas hypertension and uncontrolled blood pressure were more frequent in France (p<0.001). Mean concentrations of low-density lipoprotein cholesterol and triglycerides were significantly higher in France (p<0.001). No significant differences were observed regarding obesity, high-density lipoprotein cholesterol and diabetes. More than 97% of participants presented with at least one of the following conditions: hypertension, dyslipidaemia, diabetes, obesity or smoking. Antiplatelet agents, calcium inhibitors, diuretics and hypoglycaemic drugs were used more frequently in France, whereas angiotensin-converting enzyme inhibitors and lipid-lowering treatments were used more frequently in Spain. CONCLUSION: Prevalence of cardiovascular risk factors is high among French and Spanish patients with stable coronary heart disease, with differences between countries regarding the distribution of the various risk factors. A great proportion of patients do not reach the recommended levels for risk factor control.

Additional prognostic value of physical examination, exercise testing, and arterial ultrasonography for coronary risk assessment in primary prevention.

BACKGROUND: The choice of noninvasive tests used in primary prevention of cardiovascular diseases must be based on medical evidence. The aim of this study was to assess the additional prognostic value, over conventional risk factors, of physical examination, exercise testing, and arterial ultrasonography, in predicting a first coronary event. METHODS: A prospective cohort study was conducted between 1996 and 2004 (n = 2,709), with follow-up in 2006 (response rate 96.6%). Participants had no history or symptoms of cardiovascular disease and had a standardized physical examination, a cardiac exercise testing, and carotid and femoral ultrasonography at baseline. Incident cases of definite coronary events were recorded during follow-up. RESULTS: Over the Framingham risk score, femoral bruit, positive exercise test, intima-media thickness >0.63 mm, and a femoral plaque provided significant additional information to the prediction model. The addition of the exercise test to the traditional risk factors, then the intima-media thickness and lastly the presence of femoral plaques, produces incremental increases in the area under the receiver operating characteristic curve (0.73-0.78, P = .02) and about a 50% increase in the positive predictive value (15.8%-31.4%), with no effect on the negative predictive value (96.4%-96.9%). CONCLUSION: Physical examination, exercise testing, and arterial ultrasonography provide incremental information on the risk of coronary event in asymptomatic adults. Exercise testing and femoral ultrasonography also improve the accuracy of the risk stratification.

Accuracy of the screening physical examination to identify subclinical atherosclerosis and peripheral arterial disease in asymptomatic subjects.

OBJECTIVES: This study assessed the accuracy of the screening vascular physical examination for predicting asymptomatic peripheral arterial disease (PAD) or subclinical atherosclerosis in asymptomatic and apparently healthy subjects. METHODS: A standardized physical examination and a carotid and femoral ultrasonography were administered to 2736 men and women aged 20 to 90 years old, with no personal history of cardiovascular disease (CVD) and no complaint of neurologic, coronary, or lower limb symptom. We assessed the accuracy of auscultation for bruits and pulse palpation for identifying the presence of significant carotid stenosis, carotid plaque, femoral plaque, and ankle-brachial index (ABI) <0.9 at ultrasonography. RESULTS: The presence of a femoral bruit provided information on the presence of both an ABI <0.9 (positive likelihood ratio [+LR], 2.90; 95% confidence interval [CI], 1.63 to 5.16) and a femoral plaque (+LR, 3.23; 95% CI, 2.22 to 4.71), and this information was independent from the cardiovascular risk factors. The absence of both pedal pulses also provided additional information, beyond risk factors, on the presence of an ABI <0.9 (+LR, 3.57; 95% CI, 1.93 to 6.60). The presence of a carotid bruit did not affect the likelihood of carotid stenosis, plaque, or intima-media thickness above the median. CONCLUSION: Unlike carotid auscultation, pulse palpation and auscultation for femoral bruits provided valuable information on the presence of asymptomatic PAD and underlying atherosclerosis in apparently healthy subjects.

Is exercise testing useful to improve the prediction of coronary events in asymptomatic subjects?

OBJECTIVE: The value of exercise testing (ET) in asymptomatic subjects remains controversial and is unknown in countries with a low coronary heart disease (CHD) incidence. The aim of this study was to investigate the ability of ET to improve the prediction of a first coronary event in such a population. METHODS: Using a prospective cohort study, 1051 consecutive healthy asymptomatic adults were enrolled in a cardiovascular screening program including ET. The pre-test risk of CHD was evaluated by the 10-year Framingham risk function. Positive ET was defined as a horizontal or downsloping ST-segment depression >/=1.0 mm. The primary outcome was total coronary events (CE) occurrence, including cardiac deaths, acute myocardial infarction and stable or unstable angina. The mean follow-up period was 6 years. RESULTS: Subjects were aged 18-79 years and 36% were women. A total of 89 subjects (8.5%) had a positive ET. Positive exercise testing was associated with CE occurrence in a univariate analysis only in subjects with higher pre-test risk, defined by a 10-year Framingham risk >10.4% [hazards ratio (HR)=2.61; 95% confidence interval (CI) (1.07-6.40)]. In this risk category, ET was able to provide incremental information over the major risk factors in both men and women [risk factor-adjusted HR for positive ET=2.86; 95% CI (1.14-7.20)]. This risk excess in subjects with positive ET persisted even when a coronary revascularization was performed. Subjects with intermediate pre-test probability (10-15%) and positive ET had a post-test probability of CE largely equivalent to the probability in subjects with known CHD. CONCLUSION: Additional information provided by ET in subjects with a pre-test risk at 10-years >10% should lead to a more efficient use of risk-reducing therapies than it would be the case in this risk category with the analysis of traditional risk factors only.