A smoking-dependent risk of coronary artery disease associated with a polymorphism of the endothelial nitric oxide synthase gene.

Endothelium-dependent vasodilatation is mediated by release of nitric oxide formed by constitutively expressed endothelial nitric oxide synthase (ecNOS). We explored the distribution of polymorphism ecNOS4a/b in 549 subjects with, and 153 without, coronary artery disease in relation to smoking. In current and ex-cigarette smokers, but not nonsmokers, there was a significant excess of homozygotes for the rare ecNOS4a allele in patients with severely stenosed arteries, compared with those with no or mild stenosis. This genotype was also associated with a history of myocardial infarction. This smoking-dependent excess coronary risk in ecNOS4a homozygotes is consistent with predisposition to endothelial dysfunction.

Polymorphisms at the 5'-end of the apolipoprotein AI gene and severity of coronary artery disease.

Elevated HDL-cholesterol (C) and apo AI are associated with decreased coronary artery disease (CAD) risk. We determined distributions of two MspI polymorphisms of the apo AI gene, associated in other studies with increased HDL-C, among 644 patients aged < or = 65 years in relation to circulating lipids and CAD severity assessed angiographically. The rare allele distributions at both sites were in Hardy-Weinberg equilibrium in these patients but the base changes were not associated with HDL-C and apo AI levels. However, patients homozygous for the -75 bp substitution were more likely to have one or more significantly diseased vessels (> 50% luminal obstruction)(OR: 4.75, 95%CI: 1.10- 20.46) as also were patients with the rare +83 bp alleles (OR: 2.56, 95%CI: 1.13-5.81). While there was an additive effect of the two polymorphisms to have severe CAD (OR: 6.33, 95%CI: 1.33-30.02), the polymorphism at +83 bp remained significant in predicting CAD severity after adjusting for other variables in a logistic regression analysis (OR: 2.95, 95%CI: 1.26-6.90), which was also strongly associated with the positive family CAD history (P = 0.009). We conclude that patients with these base changes in this Australian coronary population do not have increased HDL-C and apo AI levels but do have more severe CAD.

Impact of an aggressive coronary stenting strategy on the incidence of target lesion revascularization.

Coronary stenting has been shown to reduce the incidence of target lesion revascularization (TLR) compared with balloon angioplasty in highly selected patients. However, the impact of an aggressive coronary stenting strategy in unselected patients on the overall incidence of TLR is unclear. We assessed the effect of increased stenting by comparing long-term results in consecutive patients who underwent successful percutaneous revascularization (with or without stents) during June to December 1995 (n=347) with those in June to December 1996 (n=401). Stents were used in 22.5% of patients in 1995 versus 66.1% in 1996 (p <0.0001). Mean age of the patients was 62+/-11 years (71% men) in 1995 versus 63+/-10 in 1996 (76% men) (p=NS). The 2 groups were well matched with the exception that the 1996 cohort included more patients with unstable coronary syndromes (25% in 1995 vs 34% in 1996 (p=0.003). There was no significant difference in the incidence of in-hospital adverse events. After 12 months of follow-up (complete in 95% of patients in each group), the incidence of TLR was significantly lower in the 1996 cohort than in the 1995 cohort (8.5% vs 14.7%, p=0.0075). This was mainly due to reduced requirement for repeat angioplasty in 1996 patients compared with 1995 (6.5% vs 11.8%, p=0.011). It is concluded that in an unselected patient population, an aggressive coronary stenting strategy was associated with a marked overall reduction in requirement for TLR over a 12-month period.

Genotype distribution of angiotensin-converting enzyme polymorphism in Australian healthy and coronary populations and relevance to myocardial infarction and coronary artery disease.

Angiotensin-converting enzyme is a key component of the renin-angiotensin system that plays an important role in cardiovascular regulation. An association between the angiotensin-converting enzyme insertion/deletion (I/D) polymorphism and increased coronary risk has been found in some studies but not in others. To explore this further in an Australian white population, we compared the ACE genotype distribution in 550 patients aged 37 to 65 years with coronary artery disease documented by angiography with the genotype distribution in 404 healthy school children aged 6 to 13 years. We also explored associations in the patients between the angiotensin-converting enzyme I/D polymorphism and a history of myocardial infarction and coronary artery disease severity assessed by the number of major coronary arteries with more than 50% luminal obstructions and by the Green Lane coronary score. The frequencies of the angiotensin-converting enzyme genotype in the coronary artery disease patients were 0.236 for I/I, 0.395 for I/D, and 0.369 for D/D genotypes. This distribution with an excess of the D/D genotype was significantly different (chi 2 = 23.69, P < .0001) from that in the school children, in whom the genotype distribution was in Hardy-Weinberg equilibrium (I/I, 0.21; I/D, 0.54; D/D, 0.25). There was also a significant excess of D/D genotype among patients with a history of myocardial infarction (chi 2 = 9.42, P = .009), and there was the same D/D excess in the subgroup of children (n = 60) with two or more grandparents who had had coronary artery disease. We found no associations between the angiotensin-converting enzyme polymorphism and the number of significantly stenosed coronary arteries (chi 2 = 2.069, P = .91). We conclude that the D/D genotype is a significant predictor for coronary artery disease events in the Australian white population but is not a marker for angiographically assessed coronary artery disease severity. The angiotensin-converting enzyme genotype-associated increased risk for coronary events may be mediated more by angiotensin II-induced coronary vasoconstriction than by an increase in injury-related smooth muscle cell proliferation in the coronary vasculature.

Common DNA polymorphisms at the lipoprotein lipase gene. Association with severity of coronary artery disease and diabetes.

BACKGROUND: DNA variants of the lipoprotein lipase gene are associated with changes in lipid metabolism similar to those in diabetes and may relate to the development of atherosclerotic lesions, particularly premature lesions. METHODS AND RESULTS: To determine whether lipoprotein lipase gene variants are relevant to ongoing atherogenesis, we explored relationships between two common lipoprotein lipase gene polymorphic markers, Pvu II at intron 6 and HindIII at intron 8; the severity of coronary artery disease (CAD); and lipid variables in 475 white patients 65 years of age or younger. We assessed CAD severity as the number of significantly stenosed (> 50% luminal obstruction) major coronary arteries at angiography and by the Green Lane coronary score. We found a significant association between the Pvu II polymorphism and the number of significantly diseased vessels (P = .0099) and coronary score (P = .028), with the Pvu II(-) alleles associated with less severe disease. The HindIII polymorphism was not associated with severity but had an additive effect with the Pvu II polymorphism. There was a close relationship between the Pvu II(+/+) genotype and the presence of diabetes (P = .0025), with an OR of 3.12 (95% CI, 1.30 to 7.49) compared with the Pvu II(-/-) genotype. The interaction between these polymorphisms and CAD severity (rather than occurrence) was independent of the levels of triglycerides and HDL cholesterol and of other lipid variables. There was also a dosage-dependent relationship between the Pvu II polymorphism and levels of triglyceride. The Pvu II(-) allele was associated with low levels and variances of triglycerides. CONCLUSIONS: We conclude that the lipoprotein lipase Pvu II polymorphism is significantly associated with CAD severity and with type II diabetes in CAD patients, independent of changes in circulating lipid levels. These findings may be relevant to mechanisms mediating atherogenesis.

Ioxaglate in paediatric angiocardiography.

It is generally agreed that low osmolar contrast media are better tolerated than conventional media. This study examined both tolerance and image quality of ioxaglate in a group of paediatric patients undergoing angiocardiography for congenital heart disease. A consecutive series of 50 patients (mean age 5.47 years; range 4 days-14 years) were examined. The mean dose of ioxaglate administered per patient was 2.93 mL/kg. In general, ioxaglate was well tolerated. Three patients became febrile and another developed eosinophilia. Serum creatinine rose by a mean of 10 mumol/L. Significant renal dysfunction occurred in 12 patients with an increase in creatinine of 20-30 mumol/L. In no patient, however, were these effects a significant clinical problem. Diagnostic image quality was generally considered to be good with both cine-angiography and digital subtraction angiographic techniques.

The incidence of congenital heart defects in the first year of life.

Data on the incidence of congenital heart defects (CHD) in the first year of life were collected on a cohort of infants born between 1981 and 1984 in New South Wales and the Australian Capital Territory. There was a total of 1479 cases among 343,521 births, an incidence of 4.3 per 1000 livebirths. The following results were obtained after restricting the analysis to cases diagnosed definitively by echocardiography, cardiac catheterization, operation or autopsy. A significant association was found between older maternal age and having an infant with CHD, both before (RR = 1.27, CI = 1.13, 1.44) and after (RR = 1.17, CI = 1.02, 1.33) excluding chromosomally related cases. Significant associations were found between having an infant with ventricular septal defect and Italian parentage (RR = 2.50, CI = 1.11, 5.65), and for having an infant with coarctation of the aorta and Lebanese parentage (RR = 3.82, CI = 1.71, 8.52). The incidence of CHD in this Australian population is similar to overseas studies that used comparable diagnostic criteria and ascertainment. An active surveillance system for CHD is recommended as is further investigation of the factors associated with having an infant with CHD.

Polymorphisms of the apolipoprotein E gene and severity of coronary artery disease defined by angiography.

In a recent study, we could account for only about 50% of the variance in angiographically determined severity of coronary artery disease (CAD) with use of lipid and clinical variables as predictors. To explore the possible contribution of the apolipoprotein (apo) E polymorphisms to the severity of CAD (rather than to its occurrence), we studied 424 white patients aged 65 years or less consecutively referred for coronary angiography. Among the 304 male and 120 female patients, there were 110 with no significant CAD and 118 with one, 96 with two, and 100 with three significantly diseased major coronary arteries (> 50% luminal obstruction). The allele frequencies were 0.068 for E2, 0.759 for E3, and 0.172 for E4. The E2 frequency was slightly lower and E4 higher than the frequencies reported for healthy white populations (E2: 0.072 to 0.130; E4: 0.136 to 0.160). There was a clear association between the apo E genotype and the number of significantly diseased vessels (regression coefficient = .12, P = .008). The frequency of the E4 allele increased linearly with the increase in CAD severity in both sexes (for none, one, two, and three significantly diseased vessels; female patients: 0.136, 0.161, 0.200, and 0.324; male patients: 0.136, 0.167, 0.132, and 0.229, respectively, P < .01). The frequencies of the E2 allele, on the other hand, decreased with increasing severity (for none, one, two, and three significantly diseased vessels; female patients: 0.091, 0.018, 0.050, and 0.029; male patients: 0.073, 0.089, 0.072, and 0.054, respectively, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Non-surgical mitral valvotomy.

Percutaneous transseptal mitral valvotomy was performed on 14 occasions in 13 patients; in one patient, the procedure was unsuccessful at the first attempt, but was repeated successfully. All other attempts were successful, giving a procedure success rate of 93% and a patient success rate of 100%. The only complication was transient diplopia in one patient, presumably due to a small cerebral embolus. This early experience confirms that this procedure is easily learnt, and can be performed with good results and low risk in selected patients with mitral stenosis.

The acute haemodynamic effects of oral nicardipine.

The haemodynamic effects of oral nicardipine at two different doses were assessed in fifteen patients at rest following diagnostic cardiac catheterisation. Six patients received four doses of 20 mg nicardipine hydrochloride orally every 8 h, and nine patients received four doses of 30 mg orally every 8 h. No side effects were encountered with either dose. At both dose levels, there was a significant fall in systemic vascular resistance, significant increases in heart rate and cardiac output, and no change in stroke volume index. No changes were seen in pulmonary vascular haemodynamics, and there were no significant changes in mean arterial pressure. Plasma levels of nicardipine reached a peak within 1 h. In parallel with the haemodynamic effects, the plasma concentrations achieved after the third and fourth doses were higher than after the first dose. These haemodynamic changes are consistent with a vasodilator effect, which produces a decrease in peripheral vascular resistance. It would appear that the 30 mg dose has a more potent vasodilator action than the 20 mg dose and, in the patients studied, this larger dose was not associated with any side effects.

Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation.

Modest elevations of circulating homocyst(e)ine are common in patients with vascular disease. We explored in normal and coronary artery disease (CAD) populations the distribution of a mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene that results in enzyme thermolability and reduced activity and in homocyst(e)ine elevation to assess its relevance to risk. We identified the C to T substitution at the MTHFR locus and compared the distributions of genotypes in 565 patients aged < or = 65 years without and with angiographically documented CAD and in 225 healthy subjects. In the patients, we also assessed interrelations between genotypes and CAD occurrence and severity, as well as standard risk factors. The frequency of homozygotes for the mutation was the same in patients with and without CAD and in healthy subjects (11.6%, 11.0%, and 10.7%, respectively: P > .5 for each). There was also no excess among the 419 patients with severe disease (ie, one or more vessels with > 50% luminal obstruction) compared with those with no or mild CAD (odds ratio: 1.004; 95% confidence interval: 0.59 to 1.70). Homozygosity for the mutation was also not associated with a history of myocardial infarction or the presence or severity of angina. However, body mass index increased linearly with the presence of the mutant allele (P = .005), and the mutation and hypertension were weakly associated (P = .036). We conclude that the MTHFR genotype is not a risk factor for coronary disease in this Australian population but that the strong association found with body mass index should be explored further.

Smoking: a major predictor of left ventricular function after occlusion of the left anterior descending coronary artery.

The major predictors of left ventricular function after coronary artery occlusion were assessed in 108 consecutive patients who had complete occlusion of the left anterior descending artery as the only important lesion demonstrated at angiography between June 1978 and June 1983. A scoring system was used to identify regional damage on left ventriculograms. Forty two patients were classified as having good left ventricular function and 66 as having varying degrees of impairment. Apart from a history of myocardial infarction, the only variables discriminating between those with good and those with impaired left ventricular function were the area of distribution of the artery beyond the occlusion and cigarette smoking. Hypertension, hypercholesterolaemia, family history of vascular disease, diabetes, obesity, duration of angina, age, and presence of identifiable collaterals were not discriminators. Smoking was itself significantly associated with a history of infarction; but after controlling for this, smoking exerted a significant additional effect on the amount of left ventricular damage. It is concluded that smoking is not only a risk factor for myocardial infarction in patients with single left anterior descending artery occlusion, but that it is also a major factor in determining the extent of associated left ventricular damage.

Determinants of severity of left ventricular dysfunction in Australian men and women with coronary disease aged 65 years or less.

BACKGROUND: The degree of left ventricular (LV) impairment is an important determinant of long term outcome in patients with coronary artery disease (CAD). AIM: We aimed to determine variables predictive of the severity of LV dysfunction in men and women aged 65 years or less with CAD, and to quantitate their contributions. METHODS: We documented atherogenic variables and extent of LV impairment and CAD severity at angiography in 521 consecutively studied men and women aged 65 years or less (381 males and 140 females). We assessed severity from an LV impairment score (Green Lane) and the ejection fraction. We related severity to quantitative and categorical variables which included the severity of angina (no angina, stable and unstable angina). RESULTS: The LV impairment score correlated closely (negatively) with the ejection fraction (r = -0.783, p = 0.0001). There were eight variables independently predictive of the severity of LV impairment assessed by the LV score. The variables in descending order of relative importance in predicting the LV scores were past history of myocardial infarction (MI), number of significantly diseased vessels (> 50% luminal obstruction), life-time smoking dose, log-triglycerides, total cholesterol to HDL-C ratio, hypertension, age and Body Mass Index (BMI). They were all positive relationships. Together they correctly classified the LV scores of 52.6% of the patients. Gender was not an independent contributor to the LV score when other variables were controlled. When the contributions to the variance in LV scores of past history of MI (15.4%) and number of significantly diseased vessels (2.6%) were controlled, life-time smoking dose independently explained 2.1% (p < 0.01) of the variance. The LV impairment score was 55% higher in heavy smokers than in non-smokers (p = 0.01). When we compared patients with stable and unstable angina, LV scores are higher and ejection fraction lower in the unstable angina patients consistent with them having a greater degree of LV dysfunction. CONCLUSION: We conclude that variables other than a history of MI and CAD severity contribute significantly to the variance of the degree in LV impairment in CAD patients among which the life-time smoking dose, triglycerides, TC/HDL-C, hypertension and increased BMI are all relevant to prevention, and that patients with unstable vs stable angina usually have more impaired LV function.

Percutaneous transseptal mitral valvotomy--progress report.

BACKGROUND: Percutaneous transseptal mitral valvotomy (PTMV) has been established as an alternative to surgery in the treatment of mitral stenosis. AIM: To review our experience in the first 200 attempted PTMV procedures in patients with mitral stenosis, and the short and medium term follow-up. METHODS: PTMV was attempted on 200 occasions in 189 patients with significant mitral stenosis between May 1988 and May 1994. There were 156 females and 33 males, mean age 53.5 years (range 14 to 83 years). Six patients were pregnant at the time of the procedure. RESULTS: Valve split was achieved at the initial attempt in 183/189 procedures (97%). Clinical improvement of at least one New York Heart Association (NYHA) functional class was achieved in 172/189 patients (91%). The mean mitral valve gradient (mean +/- SD) decreased from 11.5 +/- 5.1 mmHg to 4.9 +/- 4.1 mmHg, mean cardiac output rose from 3.9 +/- 1.1 L/minute to 4.4 +/- 1.4 L/minute and mean calculated mitral valve area increased from 1.0 +/- 0.3 cm2 to 2.1 +/- 0.9 cm2. Ten patients developed clinically significant mitral incompetence requiring surgical mitral valve replacement. There were two transient cerebral embolic events. Small atrial septal defects were detected echocardiographically in 42 patients, but none has been a clinical problem. There were no early deaths; there were 11 late deaths, four of which were non-cardiac. Twenty patients have had repeat PTMV for re-stenosis, four to 67 months after the first. CONCLUSIONS: PTMV provides significant haemodynamic and clinical improvement with low risk and should be considered the treatment of choice in patients with mitral stenosis.

Impact of an aggressive stenting strategy on initial and one-year follow-up costs in patients undergoing coronary angioplasty.

BACKGROUND: Although stents have been shown in randomised trials to reduce restenosis rates compared with balloon angioplasty, there are concerns regarding the cost-effectiveness of an aggressive stenting strategy. Stents were shown to increase medical costs over 12 months in the early trials. AIM: Our aim was to determine the economic impact of an aggressive stenting strategy using current stenting techniques compared with a conservative stenting strategy. METHODS: Initial and one year follow-up costs were determined in all patients who underwent successful revascularisation during June to December 1996 (aggressive stenting, n = 401), and compared to all patients treated in the corresponding months in 1995 (conservative stenting, n = 347). All patients had clinical follow-up for one year. RESULTS: The proportion of patients receiving a stent increased from 22.5% in 1995 to 66.1% in 1996 (p < 0.0001). Requirement for repeat procedures in the 1995 group compared with 1996 was coronary angiography in 31% vs 16% (p < 0.001), coronary angioplasty in 11% vs 6% (p = 0.0044) and bypass surgery in 4.8% vs 2.5% (p = 0.054). The mean initial cost of the procedure was higher in the aggressive stenting group ($4319 +/- 1276 in 1995 vs $5131 +/- 1491 in 1996, p < 0.0001), but after 12 months follow-up, total medical costs were equivalent ($5975 +/- 4143 in 1995 vs $5994 +/- 3476 in 1996, p = NS). CONCLUSION: An aggressive coronary stenting strategy is associated with higher initial costs compared with a conservative strategy, but lower costs during follow-up due to reduced need for repeat procedures, resulting in equivalent one year total medical costs.

Determinants of severity of coronary artery disease in Australian men and women.

BACKGROUND: Factors predicting the occurrence of premature coronary artery disease (CAD) may not be quantitatively the same as those predicting CAD severity, particularly in women, in whom there have been few studies. METHODS AND RESULTS: To determine factors predictive of severity of CAD and of angina pectoris, we documented atherogenic variables and the extent of CAD at angiography in 594 consecutively studied men and women aged 65 years or less. Severity was assessed from the number of involved major coronary arteries with significant (> 50%) luminal obstructions and from a coronary disease severity score. We related severity to quantitative and categorical atherogenic variables and assessed severity of angina (no angina, stable angina, or unstable angina) at the time of study in the same way. There were eight variables independently predictive of severity: in descending order of relative importance, male gender, diabetes, smoking dose, ratio of total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C), lipoprotein(a) [Lp(a)], age, positive family history, and hypertension. These correctly classified 43.3% of patients into no-, one-, two-, and three-vessel disease categories and accounted for 25.8% of variance of severity. Among 246 patients not taking lipid-lowering or beta-blocking drugs, these variables (in slightly different order) correctly classified 49.2% of patients and accounted for 36% of the variance. Among men (n = 427), seven significant variables correctly classified 39.3% of patients compared with 54.5% in women (n = 167). For those not taking the above drugs, these proportions were 49.4% and 65.4%, respectively. Among the quantitative variables, total smoking dose was the most predictive independent variable irrespective of current or ex-smoking habit and was more predictive in women than in men; of the lipid variables, high TC/HDL-C (or low HDL-C) and high Lp(a) were consistently highly predictive for all patients and in the subgroup analyses. Patients with unstable angina had higher coronary severity scores and Lp(a) levels and were more likely to have diabetes, hypertension, or a positive family history. CONCLUSIONS: We conclude that the quantitative variables most relevant to severity of premature CAD and to its prevention in Australian men and women are total amount of lifetime smoking, TC/HDL-C (or HDL-C), and Lp(a) and that patients with unstable versus stable angina usually have more severe disease and higher Lp(a).

Polymorphisms of factor V, factor VII, and fibrinogen genes. Relevance to severity of coronary artery disease.

We explored the associations between G-->A mutations of factor V and factor VII genes and the Hae III polymorphism of the fibrinogen gene and the severity of coronary artery disease (CAD), as assessed angiographically in 545 white Australian patients (388 male and 157 female) aged < or = 65 years. We also assessed the relations with other potentially atherogenic variables. Elevated fibrinogen levels were associated with more severe CAD (P < .05), but none of the factor V, factor VII, and fibrinogen DNA variants were predictive of CAD severity, as assessed by the number of significantly diseased vessels (> 50% luminal obstruction). The rare allele frequencies of factor V (A allele), factor VII (M2 allele), and fibrinogen (H2 allele) were .025, .114, and .201 for men and .022, .077, and .169 for women, respectively, and were not different from those in healthy whites. In the patient population, there was a strong, positive association between lifetime smoking dose (in pack-years) and circulating fibrinogen levels (r = .184, P = .001). This association was stronger than that between current smoking habit and fibrinogen and is consistent with a dosage effect. However, there was no significant contribution of fibrinogen genotype to fibrinogen levels in this patient population. We conclude that elevated fibrinogen levels are associated not only with the occurrence of CAD but also with more severe CAD and that measurement of DNA variants of the factor V, factor VII, and fibrinogen genes that we assessed may not provide information in predicting CAD severity in addition to that obtained by measuring circulating levels of the relevant clotting factors. There is, moreover, a positive dosage effect (in pack-years) of smoking on circulating fibrinogen levels.