Comparison of the effect of enalapril and losartan in conjunction with surgical coronary revascularisation versus revascularisation alone on systemic endothelial function.

OBJECTIVES: To investigate the effect of enalapril, losartan, and surgical coronary revascularisation on endothelial function, and the role of the angiotensin converting enzyme (ACE) insertion (I)/deletion (D) polymorphism. DESIGN: Randomised, controlled, blinded end point study. SETTING: University tertiary referral cardiac centre. PATIENTS AND INTERVENTIONS: 49 men awaiting coronary artery bypass grafting (CABG) were randomly assigned to treatment with losartan, enalapril, or control for two months before and three months after surgery. MAIN OUTCOME MEASURES: Endothelial function was blindly analysed by brachial artery flow mediated dilatation (FMD) and ACE I/D genotype was determined. RESULTS: FMD was impaired at baseline (1.0-1.7%) and after five months had improved to 5.2% with enalapril (p = 0.015), 5.0% with losartan (p = 0.0004), and 3.0% with CABG alone (p = 0.05). Patients with the II genotype had lower baseline FMD than those with DI or DD (0.1% v 1.7%, p = 0.038) and after enalapril or losartan treatment had greater improvement in FMD (mean (SEM) 7.1 (1.1)%) than patients with DI (3.1 (1.3)%, p = 0.024) or DD genotype (3.1 (1.1)%, p = 0.02). CONCLUSIONS: Enalapril and losartan, with surgical coronary revascularisation, significantly improve systemic endothelial function. Revascularisation alone produces a quantitatively smaller, but still significant, improvement. The ACE genotype significantly modulates this response. Patients with the II genotype have a more pronounced impairment in endothelial function at baseline and a greater improvement in response to treatment with these agents.

Sources of diagnostic inaccuracy of conventional versus new diagnostic criteria for myocardial infarction in an unselected UK population with suspected cardiac chest pain, and investigation of independent prognostic variables.

OBJECTIVE: To assess the degree and sources of current diagnostic inaccuracy of serial conventional cardiac markers and ECGs compared with the new diagnostic criteria for myocardial infarction, with specific reference to physician specialty and the prognostic value of troponin T. DESIGN: Prospective, blinded observational study. SETTING: University hospital. PATIENTS AND INTERVENTIONS: All suspected cardiac chest pain admissions for six months, with additional blinded measurement of CK-MB mass and troponin T. World Health Organization and new criteria myocardial infarction diagnoses were made by an expert panel. MAIN OUTCOME MEASURES: Diagnostic adjustment by expert panel; completeness of serial measurements; six months prognosis. RESULTS: A complete set of serial cardiac markers was not taken in 38.7% of patients, this being twice as likely when managed by non-cardiologists than by cardiologists (p < 0.0001). The WHO myocardial infarction diagnosis was adjusted by the expert panel in 4% of cases, this being 90% more likely in patients admitted under non-cardiologists (p = 0.026). The new criteria for myocardial infarction identified an additional 27.3% of infarcts, with a diagnostic alteration in 12.0% of the cohort; 45.2% of these cases had a potentially preventable cause for diagnostic adjustment. Only troponin T (p = 0.0004), ST depression (p = 0.003), and heart failure (p = 0.016) were independently predictive of prognosis. CONCLUSIONS: Chest pain patients appear less likely to be fully and accurately assessed by non-cardiologists than by cardiologists. The new criteria for myocardial infarction identify approximately 25% of additional patients as MI, with potential additional advantages related to simplicity of diagnostic protocols. Troponin T was the most potent predictor of six month prognosis in an unselected cohort of chest pain admissions.

Lipoprotein lipase gene variants relate to presence and degree of microalbuminuria in Type II diabetes.

AIMS/HYPOTHESIS: Lipids and lipoproteins, particularly triglyceride rich lipoproteins, could influence the development and progression of microalbuminuria in diabetes. Lipoprotein lipase gene variants have been found to correlate with lipid/lipoprotein concentrations, especially hypertriglyceridaemia. We assessed the influence of this gene on microalbuminuria in Type II (insulin-dependent) diabetes mellitus. METHODS: Microalbuminuria was determined quantitatively in 386 sequential Type II diabetic patients by measurement of the albumin-to-creatinine ratio (ACR). DNA was analysed for two common intronic LPL single nucleotide polymorphisms (Pvu II, intron 6, and Hind III, intron 8), and three common exonic mutations (Asp(9)-Asn, exon 2, Asn(291)-Ser, exon 6, and Ser(447)-Ter, exon 9). RESULTS: Individuals with P (2) P (2) (Pvu II) and H (2) H (2) (Hind III) genotypes had significantly greater ACRs ( P(2)P(2) vs P(1)P(1)+ P(1)P(2), 5.0+/-0.5 vs 3.4+/-0.3, p=0.0004 and H(2)H(2) vs H(1)H(1)+ H(1)H(2), 4.3+/-0.4 vs 3.4+/-0.3, p=0.04). Logistic regression analysis demonstrated that only the P(2)P(2) genotype ( p=0.0004), systolic BP ( p=0.008) and creatinine ( p=0.031) were independently associated with the presence of microalbuminuria/proteinuria. P(2) homozygotes were 170% more likely to have microalbuminuria or proteinuria, O.R. 2.7 (1.6-4.5, p=0.0001), 150% more likely to have microalbuminuria, O.R. 2.5 (1.5-4.3, p=0.001), and 330% more likely to have proteinuria, O.R. 4.3 (1.6-11.4, p=0.004). There were no associations of microalbuminuria with any of the exonic polymorphisms. CONCLUSION/INTERPRETATION: Genetic variants of lipoprotein lipase correlate with presence and severity of microalbuminuria in Type II diabetes, independent of effect on serum lipids. This association is only apparent in genetic variants demonstrating greatest heterozygosity.

Evaluation of patient characteristics and utilisation of invasive cardiac procedures in a UK ethnic population with unstable angina pectoris.

OBJECTIVES: To evaluate patient characteristics and utilisation of invasive cardiac procedures in a UK ethnic population with unstable angina pectoris (UAP). DESIGN: Retrospective, observational study. SETTING: Tertiary referral cardiology centre in the United Kingdom serving a large Asian ethnic population. SUBJECTS: White and Asian patients undergoing PTCA for UAP over a 2.5-year period at a UK referral cardiology centre from a comprehensive PTCA database. Data were also collated for all emergency admissions with unstable angina, or angina (type unspecified), to our institute. MAIN OUTCOME MEASURES: Demographic and angiographic characteristics of patients undergoing PTCA. Frequency of usage of invasive cardiac procedures was determined in emergency angina admissions. RESULTS: From January 1997 to July 1999, 435 White and 36 Asian patients underwent PTCA for UAP at our institute. Asian patients were on average 4.4 years younger (P=0.015), had 19.3% more diabetes (P=0.003) and 19.7% less smoking (P=0.007). Trends to more single vessel disease in Whites and more double vessel disease in Asians were observed, with similar rates of triple vessel disease. Interestingly, Asians also had trends towards more left-sided coronary artery disease and revascularisation, smaller vessels and less bail-out stenting. Asian patients were significantly less likely to undergo coronary angiography, OR 0.64 (CI 0.45-0.91, P=0.012), during the index admission, and showed a trend to less PTCA. CONCLUSIONS: Asian patients with unstable angina pectoris appear to have clinical and angiographic differences from their White counterparts, and are less likely to have invasive cardiac procedures deployed. The reasons for these observations require elucidation and the prognostic significance of these findings is uncertain.

Gene for arrhythmogenic right ventricular cardiomyopathy with diffuse nonepidermolytic palmoplantar keratoderma and woolly hair (Naxos disease) maps to 17q21.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease of unknown etiology that causes arrhythmias, heart failure, and sudden death. Diagnosis can be difficult, and this hampers investigation of its molecular basis. Forms of ARVC in which gene penetrance and disease expression are greater should facilitate genetic study. We undertook a clinical and genetic investigation of Naxos disease, originally described by Protonotarios in 1986. This disease constitutes the triad of ARVC, diffuse nonepidermolytic palmoplantar keratoderma, and woolly hair. METHODS AND RESULTS: We evaluated the population of Naxos, Greece, to identify probands, which was followed by family screening. Twenty-one affected persons from 9 families of 150 persons were identified. Linkage analysis was performed with microsatellite markers. The disease locus mapped to 17q21. A peak 2-point LOD score of 3.62 at theta=0.0 was found with a marker within intron 4 of the keratin 9 gene, a member of the type I (acidic) keratin family. A preserved homozygous disease haplotype was identified. Haplotype analysis delimited the disease interval. CONCLUSIONS: Hair and skin abnormalities were found to be reliable markers of subsequent heart disease. This suggests the presence of a single mutant gene with novel cardiac, skin, and hair function or two or more tightly linked disease genes. Recessive inheritance of Naxos disease and a founder effect were demonstrated. Identification of a fully informative genetic marker linked to the disease and uncommon in the background population may be of use as a test to identify disease gene carriers.

The Ser447-Ter mutation of the lipoprotein lipase gene relates to variability of serum lipid and lipoprotein levels in monozygotic twins.

Studies on monozygotic twins support a role for genetic determinants of plasma lipid, lipoprotein, and apolipoprotein levels. Gene variants of the enzyme lipoprotein lipase have been shown to associate with dyslipidemia and coronary artery disease. We assessed the gene-environment interaction by investigating the relationship between the lipoprotein lipase gene and plasma lipid, lipoprotein, and apolipoprotein variability and levels among 54 male monozygotic twin pairs (aged 18-28 years). The Ser447-Ter mutation (C-->G transversion) was associated with significantly smaller within-pair differences in plasma high density lipoprotein-cholesterol (CG [n = 10] vs. CC [n = 44], 3.7+/-5.3 mg/dl vs. 6.4+/-5.2 mg/dl, P < 0.03) and total cholesterol (CG [n = 10] vs. CC [n = 44], 7.9+/-9.4 mg/dl vs. 15.8+/-12.7 mg/dl, P < 0.05), indicating attenuated variability in response to environmental stimuli. This observation of a restrictive variability gene effect further supports a role for the lipoprotein lipase gene in the genetic regulation of lipids and lipoproteins and suggests that the Ser447-Ter mutation exerts multiple effects. This study also raises the possibility of a genetically determined responsiveness to dyslipidemia therapies.

A DNA variant at the angiotensin-converting enzyme gene locus associates with coronary artery disease in the Caerphilly Heart Study.

BACKGROUND: We analyzed an insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene in 1226 subjects from the Caerphilly Prospective Heart Disease Study. Amplification of genomic DNA using the polymerase chain reaction yielded the genotypes II, ID, and DD. Distribution of the polymorphism was analyzed among the whole group and within subgroups (specified following multiple risk factor analysis) for coronary artery disease (CAD) and against multiple risk factors. METHODS AND RESULTS: Allele frequencies were I = 0.413 and D = 0.587. No association was observed between the polymorphism and CAD in the whole group. Among subjects defined at lower risk of CAD by total cholesterol/HDL cholesterol (TC/HDL) ratios, we found significant associations of the DD genotype with CAD (P < .0053, n = 586 for TC/HDL < 5.654 [median] and P < .009, n = 385 for TC/HDL < 5.0 [clinical threshold]). On further exclusion of subjects with blood pressures > or = 140/90 or on hypotensive medications, the DD genotype still associated with CAD (P < .07, n = 210, TC/HDL < 5.654 and P < .016, n = 135, TC/HDL < 5.0). Further stratification of risk incorporating other risk factors, except body mass index, did not alter or enhance this association. Although similar association was observed when risk was specified by using HDL and apo B levels instead of TC/HDL, this association was lost when body mass index was included in the low-risk stratification. CONCLUSIONS: The DD genotype is a linkage marker for an etiologic mutation at or near the ACE gene that may confer risk of CAD detectable in subjects previously unidentifiable with "classic" risk factors. However, this risk may be quantitatively small among the general male population.

DNA variants at the LPL gene locus associate with angiographically defined severity of atherosclerosis and serum lipoprotein levels in a Welsh population.

Coronary artery disease (CAD) patients (n = 235), comprising minimal (CAD-, n = 124) and severe (CAD+, n = 111) CAD, were recruited on the basis of their angiographic scores. Male control subjects (n = 123) were selected randomly from the Caerphilly Heart Study cohort. Subjects were genotyped for the Ser447-Ter mutation and HindIII/Pvu II restriction fragment length polymorphisms of the lipoprotein lipase gene and investigated for associations with severity and development of CAD and lipid and lipoprotein levels. The Ser447-Ter mutation showed no significant associations with CAD or dyslipidemia but was related to favorable lipid and lipoprotein profiles. The H2H2 genotype (P < .05) and H2 allele (P = .05) were significantly more frequent in CAD+ versus CAD- and control subjects versus CAD-. H2H2 subjects, among the entire male cohort, had significantly higher levels of apolipoprotein B (P = .0002), total cholesterol (P < .004), and triglycerides (P < .04) than alternative genotypes. P2P2 associated with significantly lower high-density lipoprotein cholesterol levels (P < .01). The H2 allele had most significant associations with raised apolipoprotein B levels compared with other biochemical parameters. Our data suggest that the H2 allele may be a linkage marker for an etiologic mutation for dyslipidemia and the severity and development of atherosclerosis; this is not the Ser447-Ter mutation.

A polymorphism in the human apolipoprotein AI promoter region: a study in hypertriglyceridaemic patients.

We examined the impact of a G-->A mutation at position -75 of the apolipoprotein AI gene promoter in subjects with hypertriglyceridaemia from two racial groups, Caucasians (n = 52) and Japanese (n = 19) compared to their controls (n = 56 and n = 21 respectively). The mutation was genotyped by the polymerase chain reaction and subsequent digestion using HpaII, and BstNI. We found no significant differences in allele frequency in either control-control or case-control comparisons in European and Japanese populations. Linkage disequilibrium was observed between the mutation and the common alleles of two restriction fragment length polymorphisms, MspI and SstI located in the APOA1 and APOC3 genes, respectively, in the Japanese population. On the basis of these results, the G-75-->A mutation is unlikely to be aetiological in predisposing to hypertriglyceridaemia.

Polymorphisms of the lipoprotein lipase gene and premature atherosclerosis.

Allelic frequencies of polymorphic variants at the lipoprotein lipase gene locus have been measured in subjects with premature coronary artery disease and dyslipidaemia. One of the polymorphic variants involves a termination codon in exon 9 that produces a truncated protein whose Michaelis constants for triolein or chylomicra are identical to the native enzyme but whose Vmax for both substrates may be increased. The other informative polymorphism is a HindIII site in intron 8 that shows marked assymetric allelic distribution in subjects with hypertriglyceridaemia/low HDL syndrome and in subjects with premature coronary artery disease. It is hoped that the marker may lead to the identification of an aetiological mutation in its vicinity to account for these disease associations.