Pereira A

Usefulness of Doppler myocardial imaging for identification of mutation carriers of familial hypertrophic cardiomyopathy

Because myocyte dysfunction and disarray are early abnormalities in hypertrophic cardiomyopathy (HC), we tested if Doppler myocardial imaging (DMI) could identify systolic and diastolic dysfunction in mutation carriers (MC) (genotype positive patients without hypertrophy, defined as phenotype negative after conventional screening tests). In a single family with a missense mutation in the myosin binding protein C gene (Arg 502 Gln) we identified 5 MCs; these subjects were asymptomatic and had normal physical examination, normal electrocardiogram, treadmill stress test, ambulatory Holter electrocardiogram, and normal conventional M-mode, 2-dimensional, and Doppler echocardiography. In each patient we performed a DMI study and measured the peak velocities of the systolic (S), rapid filling (E), and atrial contraction (A) waves in the 4 sides of the mitral annulus, in 8 left ventricular segments (apical views), in the tricuspid annulus, and in 2 right ventricular segments. These data were compared with those from 10 normal volunteers matched for sex, age, and body surface. Compared with the normal volunteers, the MCs had lower left ventricular systolic velocities and higher right ventricular systolic velocities; lower diastolic rapid filling velocities; higher or similar atrial contraction velocities; reduced E/A; lower percentage of annular sides and segments with E/A >1 and lower average number of sides and/or segments with E/A >1 per patient; similar right ventricular rapid filling velocities; and similar or higher atrial contraction wave velocities. Thus, DMI detects important left and right ventricular annular and regional myocardial contraction and relaxation abnormalities independently of the presence of hypertrophy, in HC. These results show that DMI is more sensitive than conventional echocardiography and establishes a new and highly accurate method for the noninvasive screening of MCs of the disease.

Association of ADAMTS7 gene polymorphism with cardiovascular survival in coronary artery disease.

Recent genetic studies have revealed an association between polymorphisms at the ADAMTS7 gene locus and coronary artery disease (CAD) risk. Functional studies have shown that a CAD-associated polymorphism (rs3825807) affects ADAMTS7 maturation and vascular smooth muscular cell (VSMC) migration. Here, we tested whether ADAMTS7 (A/G) SNP is associated with cardiovascular (CV) survival in patients with established CAD. A cohort of 1,128 patients with angiographic proven CAD, who were followed up prospectively for a mean follow-up period of 63 (range 6-182) mo, were genotyped for rs3825807 A/G. Survival statistics (Cox regression) compared heterozygous (AG) and wild-type (AA) with the reference homozygous GG. Kaplan-Meier (K-M) survival curves were performed according to ADAMTS7 genotypes for CV mortality. Results showed that 47.3% of patients were heterozygous (AG), 36.5% were homozygous for the wild-type allele (AA) and only 16.2% were homozygous for the GG genotype. During the follow-up period, 109 (9.7%) patients died, 77 (6.8%) of CV causes. Survival analysis showed that AA genotype was an independent risk factor for CV mortality compared with reference genotype GG (HR = 2.7, P = 0.025). At the end of follow-up, the estimated survival probability (K-M) was 89.8% for GG genotype, 82.2% for AG and 72.3% for AA genotype (P = 0.039). Carriage of the mutant G allele of the ADAMTS7 gene was associated with improved CV survival in patients with documented CAD. The native overfunctional ADAMTS7 allele (A) may accelerate VSMC migration and lead to neointimal thickening, atherosclerosis progression and acute plaque events. ADAMTS7 gene should be further explored in CAD for risk prediction, mechanistic and therapeutic goals.

6C.07: INCREASE THE PREDICTIVE CAPACITY OF CORONARY RISK WITH A GENETIC SCORE.

Objective: Genes associated with coronary artery disease (CAD) and traditional cardiovascular risk factors (TCRF) present a limited individual predictive value. It is expected that the inclusion in global scores may increase the predictive ability. In genetic terms, there are no validated risk scores to predict the occurrence of cardiovascular disease or its complications. Objective: Evaluate the ability of a multifactorial genetic risk score (GRS) be able to add predictive power, for the development of CAD, to the model developed only with TCRF. Design and method: A case-control study was performed with 1321 consecutive coronary patients (mean age 53.4 ± 8.1 years, 78.8% male) and 1148 controls selected to be similar to cases in terms of gender and age. Traditional risk factors (hypertension, diabetes, dyslipidemia, smoking, obesity, sedentary lifestyle, family history) were evaluated according to the International criteria. The genetic variants were analyzed with specific primers and the GRS was determined in the entire population, based on 29 genetic polymorphisms previously associated with atherosclerotic disease in general and, in particular, with CAD. A multiplicative model was then used based on risk multiplication (odds ratio - OR) of each genotype of the 29 studied genes. Subsequently, a multivariate analysis was done with the TCRF only or the TCRF with the GRS and a ROC curve was constructed for both situations. Results: After multivariate analysis, the GRS was found to be an independent predictor for CAD (OR = 2.1; CI: 1.7–2.5; p < 0.0001). The AUC increased from 0.71 to 0.74 after the inclusion of GRS to the TCRF in the multivariate analysis (Figure). Figure. No caption available. Conclusions: In our population, the multiplicative GRS was an independent predictor for CAD. When analyzed together with traditional risk factors, it adds little predictive value. Its usefulness, in clinical practice, may be directed to the intermediate risk group, in which a possible risk reclassification can have different therapeutic measures.

EPITHELIAL SODIUM CHANNEL Y SUBUNIT POLYMORPHISM INFLUENCES ARTERIAL HYPERTENSION EMERGENCE IN A HIGH SODIUM INGESTION POPULATION: PP.21.329

Arterial Hypertension is the main cardiovascular risk factor with a prevalence of about 40% in the adult Portuguese population. The sodium and water regulation system plays an important role in the blood pressure regulation, being particularly relevant in populations with high sodium ingestion. The epithelial sodium channel, located in the distal nephron, regulates the reabsorption of sodium and water and can contribute for hypertension emergence when its activity is increased. Aim: We intend to evaluate if the epithelial sodium channel polymorphism influence arterial hypertension emergence in a population with high sodium ingestion. Methods: Case-control study including 613 individuals, 369 of which with essential hypertension (cases) and 244 without hypertension (controls). Cases and controls were matched by sex and age. Biochemical analyses and DNA extraction for genetic analyses were performed in all subjects and the epithelial sodium channel genetic polymorphism (SCNN1A(-173)G) was evaluated in each and every one of them. Statistical Analysis: All data is presented in the form of Mean ± SD. Quantitative variables and group comparisons were assessed by ANOVA and T Student tests, while qualitative variables comparisons were assessed by a Chi-square test. The corresponding case-control odds ratio was calculated, as well as the 95% confidence intervals. Finally, we applied a “Step by Step” logistic regression model in order to determine which variables were independently and significantly linked to hypertension. All statistical analyses were performed using the statistical software SPSS Windows version 14.0. Results: After Multivariate Logistic Regression with other covariate (gender, age, body mass index, diabetes, smoking, dyslipidemia) the GG genotype remained in the equation with an OR 2.4 (1.160–4.704) p = 0.018. Conclusion: According to the above results, the GG epithelial sodium channel polymorphism, SCNN1A(-173)G, influences the emergence of arterial hypertension in our population. Hypertensive subjects carrying this polymorphism, associated to an increased ability to manage sodium and water, might respond particularly well to salt restriction and to therapy with drugs like diuretics.

HUMAN PARAOXONASE GENE POLYMORPHISM AND CORONARY ARTERY DISEASE RISK

BACKGROUND Complex diseases such as coronary artery disease (CAD), hypertension and diabetes are usually caused by individual susceptibility to multiple genes, environmental factors, and the interaction between them. The paraoxonase 1 (PON1) enzyme has been implicated in the pathogenesis of atherosclerosis and CAD. Two common polymorphisms in the coding region of the PON1 gene, which lead to a glutamine (Q)/arginine (R) substitution at position 192 and a leucine (L)/methionine (M) substitution at position 55, influence PON1 activity. Studies have investigated the association between these polymorphisms and CAD, but with conflicting results. AIMS 1) To evaluate the association between PON1 polymorphisms and CAD risk; and 2) to study the interaction between PON1 polymorphisms and others in different candidate genes. METHODS We evaluated the risk of CAD associated with PON1 Q192R and L55M polymorphisms in 298 CAD patients and 298 healthy individuals. We then evaluated the risk associated with the interaction of the PON1 polymorphisms with ACE DD, ACE 8 GG and MTHFR 1298AA. Finally, using a logistic regression model, we evaluated which variables (genetic, biochemical and environmental) were linked significantly and independently with CAD. RESULTS We found that the PON1 55MM genotype was more common in the CAD population, but this did not reach statistical significance as a risk factor for CAD, while PON1 192RR presented an 80% higher relative risk compared to the population without this polymorphism. The interaction between PON1 192RR and MTHFR 1298AA, sited in different genes, increased the risk for CAD, compared with the polymorphisms in isolation (OR=2.76; 95% CI=1.20-6.47; p=0.009), as did the association of PON1 192RR with ACE DD, which presented a 337% higher risk compared to the population without this polymorphic association (OR=4.37; 95% CI=1.47-13.87; p=0.002). Similarly, the association between PON1 192RR and ACE 8 GG was linked to an even higher risk (OR=6.23; 95% CI=1.67-27.37; p<0.001). After logistic regression, smoking, family history, fibrinogen, diabetes, Lp(a) and the association of PON1 192RR + ACE 8 GG remained in the regression model and proved to be significant and independent risk factors for CAD. In the regression model the latter association had OR=14.113; p=0.018. CONCLUSION When analyzed separately, the PON1 192RR genotype presented a relative risk for CAD 80% higher than in the population without this genotype. Its association with other genetic polymorphisms sited in different genes, coding for different enzymes and belonging to different physiological systems, always increased the risk for CAD. After correction for other conventional and biochemical risk factors, the PON1 192RR + ACE 8 GG association remained a significant and independent risk factor for CAD.