B. Greg Brown

Intravenous Dipyridamole Combined With Isometric Handgrip for Near Maximal Acute Increase in Coronary Flow in Patients With Coronary Artery Disease

Twenty-four patients with coronary artery disease were studied during cardiac catheterization to determine the effects of sustained isometric handgrip exercise and intravenous dipyridamole and their combination on coronary and systemic hemodynamics and measured coronary luminal caliber. During 4 to 5 minutes of 25 percent maximal handgrip, blood pressure and heart rate increased 24 and 19 percent, respectively, coronary sinus flow increased to 1.7 x baseline value, and epicardial coronary arteries constricted to increase predicted flow resistance by 40 percent in 36 diseased arterial segments. After a 4 minute intravenous infusion of dipyridamole (0.56 mg/kg body weight), systemic pressure decreased 8 percent, heart rate increased 23 percent, coronary sinus flow increased to 2.4 x baseline value and coronary luminal caliber was unchanged. During isometric handgrip initiated 6 minutes after the infusion of dipyridamole, systemic pressure and heart rate increased to 14 and 31 percent, respectively, above control values, coronary sinus flow increased to 3.3 x baseline value (3.8 x baseline value in patients with normal anterior perfusion) and stenotic flow resistance increased by 36 percent. The response of coronary flow to the combined stresses was 68 percent greater than the response to dipyridamole alone (p less than 0.02); these flow levels exceed values previously reported for the human coronary circulation. Aminophylline plus nitroglycerin appears to assure patient safety.

Common Variants in the Promoter of the Hepatic Lipase Gene Are Associated With Lower Levels of Hepatic Lipase Activity, Buoyant LDL, and Higher HDL2 Cholesterol

Increased hepatic lipase (HL) activity is associated with small, dense, low density lipoprotein (LDL) and low high density lipoprotein2 (HDL2) cholesterol (-C) levels. A polymorphism in the promoter region of the HL gene (LIPC) is associated with HDL-C levels. To test whether this association is mediated by differences in HL activity between different LIPC promoter genotypes, the LIPC promoter polymorphism at position -250 (G-->A), HL activity, LDL buoyancy, and HDL-C levels were studied in white normolipidemic men and men with coronary artery disease (CAD). The less common A allele (frequency=0.21 and 0.25 in normal and CAD subjects, respectively) was associated with lower HL activity (P<0.005 by ANOVA) and buoyant LDL particles (P</=0.01) in both groups. Normal and CAD subjects heterozygous for the A allele had lower HL activity (by 24% and 29%, respectively) and significantly more buoyant LDL particles. Homozygosity for this allele (AA) was associated with an even lower HL activity in normal (-26%) and CAD (-46%) subjects. The A allele was associated with higher HDL2-C in CAD patients (P=0.007); heterozygotes and homozygotes for the A allele had a 92% and a 140% higher HDL2-C level (P<0.01) than did GG individuals. In a small number of normolipidemic subjects, the same trend in HDL2-C was seen. In a univariate analysis, the LIPC genotype accounted for 20% to 32% of the variance in HL levels among normal subjects and CAD patients, respectively. After adjustment for HL, the association between LIPC genotype and LDL buoyancy was no longer significant, suggesting that the effect of LIPC genotype on LDL buoyancy is mediated by its effects on HL activity. The LIPC A allele was more frequent in Japanese-Americans and African-Americans than in whites. In summary, these results suggest that variants in the LIPC promoter may significantly contribute to the variance in levels of HL activity and consequently, to the prevalence of the atherogenic small, dense, LDL particles and low HDL2-C levels.

A new digital electronic caliper for measurement of coronary arterial stenosis: Comparison with visual estimates and computer-assisted measurements☆

Visual analysis of the severity of coronary stenosis is limited by observer variability. However, more complex techniques of proved accuracy are tedious and costly. Therefore, a new digital electronic caliper (DEC) was evaluated as a potentially more accurate, rapid and less costly alternative for measuring stenosis severity. Stenosis minimum diameter (Dmin) and percent diameter reduction (% S) were measured from the screen of the cine projector using a DEC. These measurements were compared with visual estimates (VIS) by 4 experienced angiographers and with measurements made by a computer-assisted method (QCA) of proved accuracy. In routine cineangiograms from 7 patients, 10 lesions were significant (greater than 50% S) and 8 were mild (less than 50% S). Variability, the standard deviation of multiple estimates of Dmin and % S, averaged 0.09 mm and 3.1% for QCA; 0.18 mm and 5.9% for DEC; and 0.26 mm and 7.4% for VIS. Compared with QCA, the visual determination of % S significantly underestimates (-5%; p less than 0.02) mild and overestimates (+11%; p less than 0.002) significant stenosis. VIS underestimates Dmin in significant lesions by 20% (p less than 0.04). In contrast, the mean error for DEC measurement of Dmin and % S was not significantly different from 0 in either lesion group. For the entire group of lesions, and particularly in significant lesions, the mean error for measurement of these 2 indexes of disease was significantly less with DEC than with VIS. Thus, variability and error with DEC are acceptably low for clinical use.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipoprotein (a) and coronary heart disease.

The role of lipoprotein (a) in the atherosclerotic process is continually being unraveled, and many of its potential proatherogenic and prothrombotic features have already been elucidated. Whereas most studies have demonstrated a strong association between lipoprotein (a) and the presence and severity of coronary heart disease, other groups have failed to observe such a relationship, which does question the importance of this particle in promoting atherosclerosis. Evidence from a study of human coronary atherosclerosis appears to demonstrate that the pathogenicity of lipoprotein (a) is modulated by concomitant LDL-cholesterol levels. Such a modulation of the pathogenicity of lipoprotein (a) may underlie the conflicting results regarding its association with coronary heart disease. This article will examine this possibility, and will also outline the potential mechanisms through which lipoprotein (a) may interact with LDL to exert its adverse effects. As a consequence of its interaction with LDL, alternative strategies for treating high levels of lipoprotein (a) will be discussed.

Simultaneous low-density lipoprotein-c lowering and high-density lipoprotein-c elevation for optimum cardiovascular disease prevention with various drug classes, and their combinations: a meta-analysis of 23 randomized lipid trials

Purpose of review Our analysis presents an alternative hypothesis to the prevailing view that low-density lipoprotein-C is the only important target of lipid therapy. Recent findings Two recently published studies showed surprising results. In the Armed Forces Regression Study, low-density lipoprotein-C was lowered only 22% with cholystyramine, niacin and gemfibrozil. Coronary stenosis regressed, however, and the primary clinical event rate was reduced by 54%. Conversely, in the FIELD trial, the primary event rate reduction was only 11% (P = NS). These differences appeared to be explained largely by the difference in high-density lipoprotein response to these regimens (38 vs. 3%). This meta-analysis of 23 trials strongly supports the notion that the sum of percent reduction in low-density lipoprotein-C plus percent increase in high-density lipoprotein-C predicts benefits much more effectively than either lipoprotein component. Summary Epidemiology suggests that the cardiovascular event rate is reduced by nearly 1% for each 1% reduction in low-density lipoprotein-C and by at least 1% for each 1% increase in high-density lipoprotein. These effects are statistically independent; thus, for moderate lipid changes, they are additive. If this simple algorithm is proven accurate, a 30% high-density lipoprotein-C increase and a 40% low-density lipoprotein-C reduction would result in a nearly 70% CHD risk reduction – and a revolution in cardiovascular prevention.

Nicotinic Acid, Alone and in Combinations, for Reduction of Cardiovascular Risk

The current guidelines for the treatment of high risk lipid disorders do not specify a therapeutic target level of high-density lipoprotein (HDL) cholesterol for cardiovascular disease prevention in high-risk populations. However, as described in this report, there is a substantial body of evidence from basic science and epidemiologic studies and from clinical trials providing the strong, consistent message that raising HDL cholesterol by therapeutic means will effectively reduce cardiovascular risk independently of reductions in low-density lipoprotein (LDL) cholesterol. Therapeutic HDL cholesterol raising, most effectively achieved by nicotinic acid (niacin), appears to be at least as effective as comparable percentages of LDL cholesterol lowering for the reduction of atherosclerosis progression or clinical cardiovascular events, over a broad range of risk levels. The widespread adoption of this strategy awaits the results of large, ongoing controlled clinical trials of HDL cholesterol raising.

Lipid-Altering Efficacy and Safety of Ezetimibe/Simvastatin Coadministered With Extended-Release Niacin in Patients With Type IIa or Type IIb Hyperlipidemia

OBJECTIVES This study evaluated the safety and lipid-altering efficacy of ezetimibe/simvastatin (E/S) coadministered with extended-release niacin (N) in patients with type IIa or IIb hyperlipidemia. BACKGROUND Current guidelines recommend consideration of combination drug therapy to achieve optimal low-density lipoprotein cholesterol (LDL-C) lowering and broader lipid-altering effects when treating hypercholesterolemic patients at high risk for atherosclerotic cardiovascular events. METHODS In this 24-week multicenter, randomized, double-blind study, 1,220 type IIa or IIb hyperlipidemic patients were randomized to treatment with E/S (10/20 mg/day) + N (titrated to 2 g/day), or N (titrated to 2 g/day), or E/S (10/20 mg/day). Changes from baseline in LDL-C (primary) and other secondary variables were assessed in the completers and modified intent-to-treat populations. RESULTS Coadministered E/S with N resulted in significantly greater reductions in LDL-C, non-high-density lipoprotein cholesterol, triglycerides, apolipoprotein B, and lipid/lipoprotein ratios, compared with either agent alone (p < 0.001). The combination increased levels of apolipoprotein A-I and high-density lipoprotein cholesterol significantly more than E/S (p < 0.001), and reduced high-sensitivity C-reactive protein levels significantly more than N (p = 0.005). A significantly greater percentage of patients discontinued the study in the N (25.0%) and N + E/S (23.3%) groups, compared with E/S (9.6%, p < 0.001) because of clinical adverse experiences (primarily flushing). Incidences of other clinical and laboratory adverse experiences (liver-, muscle-, and gastrointestinal-related) were similar for all groups. CONCLUSIONS Combination treatment with E/S plus N showed superior lipid-altering efficacy compared with N or E/S in type IIa or IIb hyperlipidemia patients and was generally well tolerated aside from N-associated flushing. This combination offers an effective, broad, lipid-altering therapy with improvements in lipid effects beyond LDL-C in these patients. (To Evaluate Ezetimibe/Simvastatin and Niacin [Extended Release Tablet] in Patients With High Cholesterol.

Antioxidant Vitamins and Lipid Therapy: End of a Long Romance?

During the past decade, the perception flourished that lipid and antioxidant therapy were 2 independent avenues for cardiovascular protection. However, studies have shown that commonly used antioxidant vitamin regimens do not prevent cardiovascular events. We found that the addition of antioxidant vitamins to simvastatin-niacin therapy substantially blunts the expected rise in the protective high density lipoprotein (HDL)2 cholesterol and lipoprotein(A-I) subfractions of HDL, with apparent adverse effects on the progression of coronary artery disease. To better understand this effect, 12 apolipoproteins, receptors, or enzymes that contribute to reverse cholesterol transport have been examined in terms of their relationship to HDL2 and lipoprotein(A-I) levels and the potential for antioxidant modulation of their gene expression. Three plausible candidate mechanisms are identified: (1) antioxidant stimulation of cholesteryl ester transfer protein expression/activity, (2) antioxidant suppression of macrophage ATP binding cassette transmembrane transporter A1 expression, and/or (3) antioxidant suppression of hepatic or intestinal apolipoprotein A-I synthesis or increase in apolipoprotein A-I catabolism. In summary, antioxidant vitamins E and C and beta-carotene, alone or in combination, do not protect against cardiovascular disease. Their use for this purpose may create a diversion away from proven therapies. Because these vitamins blunt the protective HDL2 cholesterol response to HDL cholesterol-targeted therapy, they are potentially harmful in this setting. We conclude that they should rarely, if ever, be recommended for cardiovascular protection.

Response of normal and diseased epicardial coronary arteries to vasoactive drugs: quantitative arteriographic studies

Coronary vasodilators known to be effective in effort and vasospastic angina were studied in 93 patients undergoing catheterization for evaluation of chest pain. The ischemia-provoking stresses were isometric handgrip (25% of maximum for 4 to 5 minutes) or ergonovine maleate (0.2 mg intravenously). Hemodynamic changes and changes in angiographic diameter of epicardial coronary arteries were measured during these stresses, with and without drug administration. Drugs included intravenous diltiazem (0.25 mg/kg load + 0.003 mg/kg/min), intravenous verapamil (0.14 mg/kg load + 0.0075 mg/kg/min) and intracoronary (0.012 mg/min X 4 minutes) and sublingual (0.4 mg) nitroglycerin. From these studies, the following statistically valid conclusions were reached. First, nitroglycerin is a potent dilator of epicardial coronary arteries, increasing normal luminal area an average of 28% and luminal area in significantly stenotic segments by 29%. Second, verapamil and diltiazem are nonsignificant epicardial coronary dilators (9% and 4% luminal area increase, respectively). Similarly, diltiazem does not dilate significant coronary stenoses. Third, sustained isometric handgrip increases systemic blood pressure and heart rate by reflex activation of the sympathetic nervous system. By this means, handgrip also constricts luminal area in normal and diseased coronary segments by 20% and 22%, respectively. One result of these changes is a handgrip-induced, ischemic 56% rise in pulmonary wedge pressure in patients with significant stenosis. Fourth, intracoronary nitroglycerin, in very small doses, does not block the systemic hemodynamic response to handgrip, but prevents handgrip-induced coronary constriction and the associated ischemic left ventricular dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Types of Change in Coronary Stenosis Severity and Their Relative Importance in Overall Progression and Regression of Coronary Disease

Angiographic clinical trials of the progression and regression of obstructive coronary disease have expressed their results in terms of the average change in a large group of atherosclerotic lesions within a smaller group of patients randomized to a particular treatment. In most cases, the changes are first expressed as an average over all lesions per patient which is then averaged over all patients in each group. Since individual lesions have a variety of different characteristics in the baseline angiogram, the above averaging process tends to obscure insight into (1) the relative probability of progression and regression among lesions with different baseline characteristics, (2) the relative frequency of these high and low probability lesions in the general lesion population, and (3) the impact of therapy on progression and regression in lesions of defined baseline subtype. The Familial Atherosclerosis Treatment Study (FATS)’ examined the effect of two intensive lipid-altering strategies, as compared to a modest conventional approach, on measured disease progression in 120 patients who completed the protocol, including randomization to therapy, a baseline angiogram, and a follow-up angiogram at 2.5 years. The primary end point was change in percent stenosis averaged among the worst lesions found in each of nine proximal coronary segments in each patient. In many cases, the “worst” segmental disease was mild, or even absent. Proximal disease, per patient, averaged 35% diameter stenosis (%S) at baseline. It increased (net progression) by 2.10 %S among the conventionally treated patients and improved (net regression) by -0.75 and -0.85 in each of the two intensively treated groups.’ We have examined the contribution to this averaged net