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The efficacy, safety, and tolerability of a moderate dose, 3-drug lipid-lowering regimen were evaluated among 29 male patients with hyperlipidemia and coronary artery disease. In an initial 12-month phase, regular niacin, 500 mg qid, lovastatin, 20 mg bid, and colestipol, 10 g/bid, were given with dose adjustment for lipid targets and side effects. This was followed by 2 random sequence crossover phases (8 months each) alternating regular niacin with a polygel controlled-release formulation of niacin for use in this regimen. Lipid, lipoprotein, apoprotein, and clinical chemistry determinations were obtained at baseline, during the initial phase, at the 2 crossover phases, and at 6 weeks after therapy. A final questionnaire queried specific side effects and overall preferences. Low-/high-density lipoprotein (LDL/HDL) changed from means of 215/46 mg/dl at baseline, to 94/59 mg/dl after run-in, to 85/52 mg/dl after 8 months of controlled-release niacin, and to 98/56 mg/dl after 8 months of regular niacin (regular niacin vs controlled-release niacin, p <0.005/<0.05). The target of LDL < or = 100 mg/dl was achieved at 8 months by 83% of these patients with controlled-release niacin and by 52% with regular niacin (p <0.01). Compliance was 95% with controlled-release niacin versus 85% with regular niacin (p <0.001). The controlled-release niacin and regular niacin regimens did not differ in terms of uric acid, glucose, insulin, or asparate aminotransferase levels. Overall, 21% of patients called the 3 drugs "very easy" and 72% "fairly easy" to take. The controlled-release niacin-containing regimen was preferred by 21 patients and the regular niacin by 4. In conclusion, these regimens achieve striking lipid changes among hyperlipidemic patients. Controlled release is the preferred niacin preparation in terms of LDL reduction, compliance, patient preference, and achieving the National Cholesterol Education Program guideline of LDL < or = 100 mg/dl. The 2 niacin preparations did not differ in evidence of toxicity. [ABSTRACT FROM AUTHOR]

We examined the impact of metabolic syndrome (MS) on coronary stenosis progression and major cardiovascular (CV) events and investigated the mitigating effects of low-density lipoprotein (LDL) cholesterol lowering and LDL cholesterol lowering plus high-density lipoprotein (HDL) cholesterol increasing. This analysis combined individual patient data from 445 subjects who participated in 3 double-blinded, randomized, placebo-controlled trials (FATS, HATS, and AFREGS) comparing intensive lipid therapy to placebos on coronary stenosis progression by quantitative coronary angiography and on major CV events. The primary end points were change in mean proximal coronary diameter stenosis (Delta%S(prox)) over 3 years and the frequency of the predefined composite of coronary artery disease death, nonfatal myocardial infarction, stroke, and revascularization due to worsening ischemia. Patients with MS had 50% more rapid coronary stenosis progression and 64% increased CV event frequency compared to those without. More rapid coronary stenosis progression was significantly and independently associated with a 3.5-fold increased event risk (p <0.001). Combination lipid therapy significantly decreased stenosis progression by 83% (Delta%S(prox) 0.5 vs 2.9, p <0.001) in patients with MS and induced a small net regression in those without (Delta%S(prox) -0.3 vs 2.0, p <0.001). Combination therapy decreased the event rate by 54% (13% vs 28%, p = 0.03) in those with MS and by 82% (3% vs 17%, p = 0.002) without. On average, each 10% decrease in LDL cholesterol or 10% increase in HDL cholesterol was significantly associated with a 0.3 Delta%S(prox) decrease. Each 10% decrease in LDL cholesterol or 10% increase in HDL cholesterol was associated with 11% (p = 0.02) or 22% (p <0.001) event risk decrease. In conclusion, patients with MS have significantly more rapid coronary stenosis progression and a higher frequency of CV events. Greater stenosis progression rate is associated with a higher event rate. LDL cholesterol-lowering and HDL cholesterol-increasing therapies independently and significantly decrease coronary stenosis progression and decrease CV events. [ABSTRACT FROM AUTHOR]

Two large studies in populations selected for cardiovascular disease (CVD) demonstrated that raising high-density lipoprotein (HDL) cholesterol with niacin added to statin therapy did not decrease CVD. We examine the association of lipoprotein subfractions with niacin and changes in coronary stenosis and CVD event risk. One hundred and seven patients from 2 previous studies using niacin in combination with either statin or bile acid-binding resin were selected to evaluate changes in lipoproteins separated by density-gradient ultracentrifugation to progression of coronary artery disease as assessed by quantitative coronary angiography. Improvement in coronary stenosis was significantly associated with the decrease of cholesterol in the dense low-density lipoprotein (LDL) particles and across most of the intermediate density lipoprotein (IDL) and very low density lipoprotein particle density range, but, not with any of the HDL fraction or of the more buoyant LDL fractions. Event-free survival was significantly associated with the decrease of cholesterol in the dense LDL and IDL; there was no association with changes in cholesterol in the HDL and buoyant LDL fractions. Niacin combination therapy raises HDL cholesterol and decreases dense LDL and IDL cholesterol levels. Changes in LDL and IDL are related to improvement in CVD. Lipoprotein subfraction analysis should be performed in larger studies utilizing niacin in combination with statins., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Although the effect of niacin on the glucose levels in subjects with diabetes mellitus has been investigated, niacin's effects on the glucose levels and atherosclerosis in subjects with normal glucose levels have not been well established. We examined the effect of niacin on the glucose levels, coronary stenosis progression using quantitative coronary angiography, and clinical events in 407 subjects who had a baseline glucose level <100 mg/dl and were enrolled in the Familial Atherosclerosis Treatment Study (FATS), HDL-Atherosclerosis Treatment Study (HATS), Armed Forces Regression Study (AFREGS), or Carotid Plaque Composition by MRI during lipid-lowering (CPC) study testing active niacin therapy. Although the fasting glucose levels increased significantly within 3 years in both subjects treated with niacin (from 85.6 ± 9.5 to 95.5 ± 19.7 mg/dl, p <0.001) and without niacin (from 85.2 ± 9.6 to 90 ± 17.9 mg/dl, p = 0.009), those treated with niacin had a significantly larger increase in glucose levels than those not taking niacin (9.88 vs 4.05 mg/dl, p = 0.002). Overall, 29% of subjects developed impaired fasting glucose within 3 years. Incident impaired fasting glucose was significantly more likely to be observed in subjects treated with niacin than in those who were not. However, the frequency of new-onset diabetes mellitus did not differ significantly between the 2 groups (5.6% vs 4.8%, p = 0.5). Niacin-treated subjects compared to untreated subjects had significantly less change in mean coronary stenosis (0.1 ± 0.3% vs 2 ± 12%, p <0.0001) and less major cardiovascular events (8% vs 21%, p = 0.001). In conclusion, the use of niacin for 3 years in subjects with normal baseline glucose levels was associated with an increase in blood glucose levels and the risk of developing impaired fasting glucose, but not diabetes mellitus, and was associated with a significantly reduced incidence of coronary stenosis progression and major cardiovascular events., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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.

Previous studies of electron-beam tomography (EBT) have correlated coronary calcium scores with simplistic visual estimates of disease severity. In a clinical trial designed to evaluate 2 treatment strategies in coronary artery disease (CAD) patients with low levels of high-density lipoprotein cholesterol, we used quantitative coronary angiography to measure composite proximal stenosis burden from the baseline coronary angiogram and assessed the traditional Framingham risk variables in 146 patients. Stenosis burden is the sum, per patient, of percent stenosis for the worst lesion found in each of 9 standard proximal coronary segments. EBT estimates of coronary calcium (Agatston score, calcium volume score) were obtained for 115 of these patients. Stenosis burden was correlated with the calcium scores and risk variables. The best traditional correlates of stenosis burden were smoking status (r = 0.31, p = 0.001), prior myocardial infarction (r = 0.24, p = 0.005), body mass index (r = 0.23, p = 0.005), pack-years smoking (r = 0.20, p = 0.05), and age (r = 0.17, p = 0.04). With adjustment for age, all these correlations improved (eg, body mass index x age [r = 0.28, p = 0.001]). In addition, total cholesterol x age (r = 0.22, p = 0.008), fibrinogen x age (r = 0.19, p = 0.03), and systolic blood pressure x age (r = 0.18, p = 0.03) became significant correlates. Spearman correlations of the calcium scores with stenosis burden were considerably greater (Agatston: r = 0.62, p <0.0001; calcium volume: r = 0.63, p <0.0001). In multivariate regression analysis, calcium score, body mass index, and history of myocardial infarction were independent correlates of stenosis burden (R(2) = 0.45). At a given point in time, the EBT coronary calcium scores are greatly superior to the Framingham risk factors in predicting the measured proximal stenosis burden. Agatston and calcium volume scores are comparably predictive of stenosis burden.

Trials of lipid lowering by various methods have clearly demonstrated the benefits, clinically and angiographically. Evidence of slowed arterial disease progression and even regression has been convincing but modest, at best. For example, among those treated intensively in the Familial Atherosclerosis Treatment Study (FATS), the mean improvement in proximal stenosis severity was <1% per patient, and only 12% of all lesions showed convincing regression. Despite these modest arterial benefits, the associated reductions in major cardiovascular events have been surprisingly great (24-35% in 3 recent large trials and > or =50% in angiographic trials using combination therapies). The process of plaque disruption helps explain this discrepancy. Disruption can be predicted by a large accumulation of core lipid in the plaque and a high density of lipid-laden macrophages in its thinned fibrous cap. Lesions with these characteristics comprise only 10-20% of the overall lesion population but account for 60-90% of the acute clinical events. Lipid-lowering therapy has beneficial effects on these "high-risk" features of plaque morphology. The composite of data presented here supports the hypothesis that lipid-lowering therapy selectively depletes lipids from this relatively small but dangerous subgroup of fatty lesions, effectively stabilizing them.

Patients in the original Familial Atherosclerosis Treatment Study (FATS) cohort were subgrouped into those with triglyceride levels < or = 120 mg/dL (n = 26) and those with triglyceride levels > or = 190 mg/dL (n = 40). Their therapeutic responses to niacin plus colestipol, lovastatin plus colestipol, colestipol alone, or placebo were determined. Therapeutic response was also determined in the same 2 triglyceride subgroups (n = 12 and n = 27, respectively) of patients selected for low levels of high-density lipoprotein (HDL) cholesterol and coronary artery disease. These triglyceride criteria were chosen to identify patient subgroups with high likelihood of "pattern A" (normal-size low-density lipoprotein [LDL] particles and triglyceride < or = 120 mg/dL) or "pattern B" (small dense LDL and triglyceride > or = 190 mg/dL). Our findings in these small patient subgroups are consistent with the emerging understanding that coronary artery disease patients presenting with high triglyceride levels have lower HDL-C, smaller less buoyant LDL-C, and greater very low-density lipoprotein (VLDL) cholesterol and VLDL apolipoprotein B, and are more responsive to therapy as assessed by an increase in HDL-C and reduction in triglycerides, VLDL-C, and VLDL apolipoprotein B. In the FATS high-triglyceride subgroup with these characteristics, a tendency toward greater therapeutic improvement in coronary stenosis severity was observed among those treated with either of the 2 forms of intensive cholesterol-lowering therapy. This improvement is associated with therapeutic reduction of LDL-C and elevation of HDL-C, but also appears to be associated with drug-induced improvement in LDL buoyancy.

The effect of intravenous verapamil on systemic and coronary hemodynamic function was studied at cardiac catheterization in 12 patients with coronary artery disease. Verapamil was administered as a 2-minute bolus (0.145 mg/kg) followed by an infusion (0.005 mg/kg/min). Cardiac output and coronary sinus blood flow were measured by thermodilution techniques. Caliber of the large coronary arteries and of diseased segments was determined from the coronary angiogram using a computer-assisted method. Verapamil reduced mean arterial pressure 14% (p less than 0.001), systemic vascular resistance 21% (p less than 0.01), and stroke work index 16% (p less than 0.001). Coronary vascular resistance decreased 24% (p less than 0.01) with a small increase in coronary sinus blood flow (+13%, difference not significant [NS]). Myocardial oxygen consumption determined in 5 patients showed no significant change with verapamil. Luminal area in 39 coronary lesions was measured in the "normal" portion of the diseased segment and at its maximal constriction, and an estimate of flow resistance in the stenosis was computed. Overall, 50% of "normal" and of diseased coronary segments dilated significantly with verapamil. Stenosis dilation resulted in an average 14% reduction (p less than 0.01) in estimated flow resistance. In 8 patients, the luminal changes (n = 27) induced by sublingual nitroglycerin were compared with those induced by verapamil. Nitroglycerin induced a significantly greater increase in coronary caliber in both normal and diseased segments; estimated stenosis flow resistance decreased 28% with nitroglycerin compared with 14% with verapamil (p less than 0.01). Thus, verapamil moderately dilates the systemic and coronary small vessel resistance bed without apparently increasing myocardial metabolic demand. Furthermore, verapamil mildly dilates large coronary conductance vessels in both "normal" and diseased segments, although significantly less than does nitroglycerin.

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.

The response to sublingual isosorbide dinitrate (ISDN) was studied in 10 men with suspected coronary artery disease undergoing coronary arteriography. A Swan-Ganz catheter was placed in the pulmonary artery to record hemodynamic response. Diseased coronary segments were identified during routine Judkins selective coronary angiograms. Sublingual isosorbide dinitrate (ISDN) (5 or 10 mg) was then given with the catheters in place. Multiple sequential single-view coronary angiograms and pulmonary and systemic hemodynamic responses were recorded over 30 minutes after drug administration. At 30 minutes, there was a 53% reduction (p less than 0.01) in pulmonary capillary wedge pressure and a 15% decrease (p less than 0.05) in systemic and pulmonary vascular resistance, with a net 13% decrease (p less than 0.01) in cardiac output and 20% decrease (p less than 0.01) in mean arterial pressure. Quantitative arteriography demonstrated substantial dilation of luminal cross-sectional area in both normal and diseased coronary arterial segments. Normal epicardial segments were grouped according to luminal area (1 to 4, 4 to 8 and more than 8 mm2) and demonstrated maximal area dilation at 10 minutes of 55% (p less than 0.01), 29% (p less than 0.01) and 16% (p less than 0.05), respectively. Diseased epicardial segments (stenosis 50% or greater) dilated 51% (p less than 0.01) at 10 minutes. Calculated stenosis resistance decreased 40% (p less than 0.01). Diseased segments in small and middle-sized arteries (1 to 8 mm2) are 4 times more reactive than those in larger arteries (more than 8 mm2), with peak dilation of 77 vs 21% (p less than 0.01) at 30 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether arteriographic dimensions of the acutely recanalized coronary lumen provide information about regional perfusion or clinical outcome, quantitative arteriography was used to measure minimum luminal diameter achieved with intracoronary streptokinase administration in 44 patients with acute myocardial infarction (AMI). Degree of coronary reperfusion was independently assessed visually using the criteria applied in the multicenter Thrombolysis in Myocardial Infarction study. Minimum diameter and qualitative reperfusion grade were both assessed from 172 coronary injections during thrombolysis. Partial perfusion (grade 1 or 2) was seen in 95 of 135 injections (70%) in which the minimum diameter was less than 0.6 mm and complete perfusion (grade 3) was seen in 35 of 37 injections (95%) in which it was 0.6 mm or more (p less than 0.001). Repeat cardiac catheterization was performed at 5.5 +/- 4.9 weeks after AMI (n = 20). When vessels were opened acutely to a minimum diameter of less than 0.6 mm, 5 of 12 vessels (42%) were reoccluded at the time of restudy and 8 of 29 patients (28%) died within 12 months. By contrast, 0 of 8 vessels (0%) were reoccluded when the artery was opened to a diameter of at least 0.6 mm (difference not significant), and only 1 of 15 patients (7%) died (p less than 0.05). Of the patients with grade 1 o r 2 perfusion at the end of the thrombolytic infusion, 7 of 19 (37%) died within 12 months and 2 of 4 vessels (50%) reoccluded; of the patients with grade 3 perfusion, 2 of 25 (8%) died (p less than 0.05) and 2 of 16 vessels (13%) reoccluded (difference not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

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)

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)

Coronary arteriography is the most commonly used technique for documenting the immediate percutaneous transluminal coronary angioplasty result and for follow-up of the dilated arterial segment for restenosis within 6 months (which occurs in about 25% to 35% of cases). Acute success in dilation of the coronary lesion is likely if there is at least a resultant 1.3 mm2 minimum lumen area, equivalent to a 1.3 mm mean minimum lumen diameter, or about a 50% diameter stenosis of a typical proximal vessel. The measurement methods applied to this problem include a digital caliper, computer-assisted border recognition techniques and a video-densitometric approach to estimation of lumen area. Calipers are recommended because of their simplicity, precision and accuracy for the routine assessment of angioplasty result. Border-recognition techniques require considerable operator input to distinguish true flow channels from cul de sacs in the dissected segment. The automated scanning videodensitometry approach has theoretical appeal and has shown promise in preliminary reports; however, there is the potential for large measurement errors in the setting of dissection. Further, certain qualitative morphologic features of the dilated segment, such as longitudinal or transverse dissection or intraluminal thrombus, may effectively contribute to the prediction of acute complications and may be useful predictors of late restenosis. Because these features are best appreciated at increased arteriographic magnification, further high resolution studies will be necessary to better understand their importance.