Assessment of dioxin and dioxin-like compounds in mainstream smoke from selected US cigarette brands and reference cigarettes.

Mainstream cigarette smoke (MSS) from 12 US cigarette brands and two reference cigarettes was evaluated to determine concentrations of dioxins (i.e., polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (PCBs)). The study included three 'tar' ranges based on Federal Trade Commission (FTC) determination: Low Yield (LY) < or = 5.5, Medium Yield (MY) 9.6-12.2, and High Yield (HY)> or = 14.5 mg/cig. Of the brands studied, the HY cigarettes yielded the greatest mean concentrations of 2005 World Health Organization Toxic Equivalents (WHO-TEQs) on a per cigarette basis. WHO-TEQ levels in LY cigarettes were significantly lower than for HY cigarettes (p=0.039) on a yield per cigarette basis and WHO-TEQ concentrations correlated with 'tar' yield (r=0.73, p=0.007), as did concentration on a WHO-TEQ per body mass per day basis (r=0.73, p=0.007). However, a statistically significant relationship was not observed between 'tar' yield levels and WHO-TEQ concentrations on a per mg Total Particulate Matter (TPM) basis. Concentrations for all brands tested ranged from 0.44 to 3.88 fg WHO-TEQ/mg TPM. Maximum daily exposure estimates calculated from this range (0.004-0.074 pg WHO-TEQ/kg bw/day) are below the current WHO Tolerable Daily Intake range of 1-5 pg/kg bw/day.

Plasma phospholipid transfer protein activity in patients with low HDL and cardiovascular disease treated with simvastatin and niacin.

Plasma phospholipid transfer protein (PLTP) is an important modulator of high-density lipoprotein (HDL) metabolism, regulating its particle size, composition, and mass. In patients with low HDL and cardiovascular disease (CVD), plasma PLTP activity is positively correlated with the concentration of HDL particles containing apo A-I but not apo A-II (Lp(A-1)). We recently completed a study to determine the effect of simvastatin and niacin (S-N) therapy on disease progression/regression in these patients, and found that this therapy selectively increased Lp(A-I). To determine if PLTP was also increased with this drug therapy, we measured the PLTP activity in the plasma of 30 of these patients obtained at baseline and after 12 months of therapy, and compared the changes to a similar group of 31 patients who received placebo for the drugs. No significant increase in PLTP activity was observed in either group of patients. However, changes in apo A-I and A-II between these two time points were correlated with the corresponding change in PLTP activity. The correlation coefficients were r=0.57 (P=0.001) and r=0.43 (P=0.02) for apo A-I, and r=0.54 (P=0.002) and r=0.41 (P=0.02) for apo A-II in the placebo and S-N group, respectively. At baseline, PLTP activity correlated positively with the percent of plasma apo A-I associated with Lp(A-I) (r=0.38, P=0.04) and the amounts of apo A-I in these particles (r=0.43, P=0.02). These relationships persisted in patients who took placebo for 12 months (r=0.46, P=0.009 and r=0.37, P=0.04, respectively), but was attenuated in those treated with S-N. These data indicate that S-N-induced increase in Lp(A-I) was PLTP-independent. It also confirms our previous observation that an interrelationship exists between PLTP and apo-specific HDL particle subclasses in CVD patients with low HDL, and that this relationship is altered by drug intervention.

Evidence for a new pathophysiological mechanism for coronary artery disease regression: hepatic lipase-mediated changes in LDL density.

BACKGROUND: Small, dense LDL particles are associated with coronary artery disease (CAD) and predict angiographic changes in response to lipid-lowering therapy. Intensive lipid-lowering therapy in the Familial Atherosclerosis Treatment Study (FATS) resulted in significant improvement in CAD. This study examines the relationship among LDL density, hepatic lipase (HL), and CAD progression, identifying a new biological mechanism for the favorable effects of lipid-altering therapy. METHODS AND RESULTS: Eighty-eight of the subjects in FATS with documented coronary disease, apolipoprotein B levels >/=125 mg/dL, and family history of CAD were selected for this study. They were randomly assigned to receive lovastatin (40 mg/d) and colestipol (30 g/d), niacin (4 g/d) and colestipol, or conventional therapy with placebo alone or with colestipol in those with elevated LDL cholesterol levels. Plasma hepatic lipase (HL), lipoprotein lipase, and LDL density were measured when subjects were and were not receiving lipid-lowering therapy. LDL buoyancy increased with lovastatin-colestipol therapy (7.7%; P<0.01) and niacin-colestipol therapy (10.3%; P<0.01), whereas HL decreased in both groups (-14% [P<0.01] and -17% [P<0.01] with lovastatin-colestipol and niacin-colestipol, respectively). Changes in LDL buoyancy and HL activity were associated with changes in disease severity (P<0.001). In a multivariate analysis, an increase in LDL buoyancy was most strongly associated with CAD regression, accounting for 37% of the variance of change in coronary stenosis (P<0.01), followed by reduction in apolipoprotein Bl (5% of variance; P<0.05). CONCLUSIONS: These studies support the hypothesis that therapy-associated changes in HL alter LDL density, which favorably influences CAD progression. This is a new and potentially clinically relevant mechanism linking lipid-altering therapy to CAD improvement.

Common hepatic lipase gene promoter variant determines clinical response to intensive lipid-lowering treatment.

BACKGROUND: The common -514 C-->T polymorphism in the promoter region of the hepatic lipase (HL) gene affects HL activity. The C allele is associated with higher HL activity, more dense and atherogenic LDL, and lower HDL(2) cholesterol. Intensive lipid-lowering therapy lowers HL activity, increases LDL and HDL buoyancy, and promotes coronary artery disease (CAD) regression. We tested the hypothesis that subjects with the CC genotype and a more atherogenic lipid profile experience the greatest CAD regression from these favorable effects. METHODS AND RESULTS: Forty-nine middle-aged men with dyslipidemia and established CAD who were undergoing intensive lipid-lowering therapy were studied. Change in coronary stenosis was assessed by quantitative angiography, HL polymorphism by polymerase chain reaction amplification, HL activity by (14)C-labeled substrate, and LDL buoyancy by density-gradient ultracentrifugation. The response to lipid-lowering therapy was significantly different among subjects with different HL promoter genotypes. Subjects with the C:C genotype had the greatest decrease in HL activity (P<0.005 versus TC and TT by ANOVA) and the greatest improvement in LDL density (P<0.005) and HDL(2)-C (P<0.05) with therapy. These subjects had the greatest angiographic improvement, with 96% of them experiencing CAD regression, compared with 60% of TC and none of the TT patients (P:<0.001). CONCLUSIONS: -In middle-aged men with established CAD and dyslipidemia, the HL gene -514 C-->T polymorphism significantly predicts changes in coronary stenosis with lipid-lowering treatment that appear to involve an HL-associated effect on LDL metabolism. This study identifies a gene polymorphism that strongly influences the lipid and clinical response to lipid-lowering drugs.

Benefits of lipid-lowering therapy in men with elevated apolipoprotein B are not confined to those with very high low density lipoprotein cholesterol.

OBJECTIVES: Do the benefits of intensive lipid-lowering therapy extend to patients with only borderline or moderately elevated levels of low density lipoprotein (LDL) cholesterol? BACKGROUND: The merits of the present LDL cholesterol treatment goal of < or = 100 mg/dl need to be clarified for patients without high levels of LDL cholesterol, particularly for those patients previously classified as having only borderline high (130 to 159 mg/dl) or desirable (101 to 130 mg/dl) levels. METHODS: Disease change and clinical events were examined in LDL cholesterol subgroups in the Familial Atherosclerosis Treatment Study (FATS) trial, a randomized, blinded, quantitative arteriographic comparison of one conventional and two intensive lipid-lowering strategies in men with coronary artery disease, a positive family history and apolipoprotein B > or = 125 mg/dl. The primary end point, disease change per patient, was measured as the mean change in severity of stenosis (delta %SProx) among nine standard proximal segments. RESULTS: Of the 120 patients completing the 30-month protocol, 60 had a baseline LDL cholesterol < 90th percentile (mean LDL cholesterol 152 mg/dl) and 60 > 90th percentile (mean LDL cholesterol 221 mg/dl). Thirty-one patients had levels < 160 mg/dl (mean LDL cholesterol 134 mg/dl) and 89 > 160 mg/dl (mean LDL cholesterol 205 mg/dl). Patients with LDL cholesterol < 90th percentile benefited angiographically from therapy (delta %SProx = -1.5% diameter stenosis [regression] during intensive therapy vs. +2.3% diameter stenosis [progression] during conventional therapy, p < 0.01), as did patients with LDL cholesterol < 160 mg/dl (delta %SProx = -4.2% vs. +3.3% diameter stenosis, p = 0.0001). By comparison, angiographic benefit was less pronounced among those entering with very high LDL cholesterol (delta %SProx = -0.2% vs. +1.9% diameter stenosis, p = 0.07) or with LDL cholesterol > or = 160 mg/dl (delta %SProx = +0.2% vs. +1.6% diameter stenosis, p = 0.13). Intensive therapy resulted in a statistically significant reduction in clinical events only in the subgroup with baseline LDL cholesterol < 90th percentile (2 of 42 vs. 8 of 29 patients initially enrolled, p = 0.01) and a trend toward fewer events in patients with LDL cholesterol < 160 mg/dl (2 of 20 vs. 6 of 15 patients, p = 0.05). No such difference was seen in the higher LDL cholesterol subgroups. CONCLUSIONS: Treatment benefit in the FATS trial was not confined to patients with very high levels of LDL cholesterol and was in fact particularly evident in those patients with levels < 160 mg/dl. Such patients should be considered more likely, not less, to benefit from intensive lipid-lowering therapy.

Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL.

One strategy for treating coronary artery disease (CAD) patients with low HDL cholesterol (HDL-C) is to maximally increase the HDL-C to LDL-C ratio by combining lifestyle changes with niacin (N) plus a statin. Because HDL can prevent LDL oxidation, the low-HDL state also may benefit clinically from supplemental antioxidants. Lipoprotein changes over 12 months were studied in 153 CAD subjects with low HDL-C randomized to take simvastatin and niacin (S-N), antioxidants (vitamins E and C, beta-carotene, and selenium), S-N plus antioxidants (S-N+A), or placebo. Mean baseline plasma cholesterol, triglyceride, LDL-C, and HDL-C levels of the 153 subjects were 196, 207, 127, and 32 mg/dL, respectively. Without S-N, lipid changes were minor. The S-N and S-N+A groups had comparably significant reductions (P

Effects of prolonged intensive lipid-lowering therapy on the characteristics of carotid atherosclerotic plaques in vivo by MRI: a case-control study.

High-resolution magnetic resonance imaging (MRI) with flow suppression not only provides useful information on luminal and wall areas of the carotid artery but also can identify the principal tissue components of the carotid atherosclerotic plaque. The effects of intensive lipid-lowering therapy on these MRI tissue characteristics were examined in patients with coronary disease (CAD). Eight CAD patients who have been receiving intensive lipid-lowering treatment (niacin 2.5 g/d, lovastatin 40 mg/d, and colestipol 20 g/d) for 10 years in the Familial Atherosclerosis Treatment Study (FATS) follow-up were randomly selected from among 60 such treated patients. Eight CAD patients who were matched to the treated patients for age (+/-3 years), baseline low density lipoprotein (+/-5 mg/dL), and triglycerides (+/-50 mg/dL) but who had never been treated with lipid-lowering drugs were selected as controls. For each of these 32 carotid arteries, luminal and plaque areas were measured by planimetry, in a blinded protocol, from the magnetic resonance image that showed most plaque. Fibrous tissue, calcium, and lipid deposits were identified on the basis of established criteria. Plaque composition was estimated as a fraction of total planimetered area. Patients treated with 10-year intensive lipid-lowering therapy, compared with control subjects, had significantly lower low density lipoprotein cholesterol levels (84 versus 158 mg/dL, respectively; P<0.001) and higher high density lipoprotein cholesterol levels (51 versus 37 mg/dL, respectively; P<0.001). As a group, treated patients, compared with untreated control subjects, had a smaller core lipid area (0.7 versus 10.2 mm(2), respectively; P=0.01) and lipid composition (1% versus 17%, respectively). Group differences in luminal area (55 [treated] versus 44 [control] mm(2), P=NS) and plaque area (58 [treated] versus 64 [control] mm(2), P=NS) tended to favor treatment. MRI appears useful for estimating carotid plaque size and composition. Hyperlipidemic CAD patients frequently (97%) have at least moderate (>/=40% area stenosis) carotid plaque. In this case-control study, prolonged intensive lipid-lowering therapy is associated with a markedly decreased lipid content, a characteristic of clinically stable plaques.

Coronary vasospasm. Observations linking the clinical spectrum of ischemic heart disease to the dynamic pathology of coronary atherosclerosis.

Patients with angina, myocardial infarction, and sudden death almost always have demonstrable coronary atherosclerosis. Furthermore, there is mounting evidence that coronary artery "spasm" is a contributing feature of these different coronary ischemic syndromes. Using quantitative angiography and two modes of alpha-adrenergic stimulation in patients with spontaneous most angina, vasomotor hyperreactivity was shown to be localized only to the region of a preexisting coronary atheroma. These observations support the hypothesis that a dynamic interaction between the histopathologic features of coronary atherosclerosis and "normal" amounts of coronary smooth-muscle shortening accounts for the clinical features in the great majority of cases in the spectrum of ischemic heart disease. There are stenosis, each with different therapeutic implications.

Differential replication and pathogenic effects of HIV-1 and HIV-2 in Macaca nemestrina.

OBJECTIVE: HIV-1 and HIV-2 isolates representing various geographic regions and distinct viral subtypes were examined for their ability to establish both in vitro and in vivo productive infections of Macaca nemestrina (pigtail macaque) peripheral blood mononuclear cells. METHODS: Animals were inoculated with either autologous cell-associated or cell-free viral preparations of selected isolates. HIV-specific immune responsiveness, hematologic changes, genetic variation, and virus burden were monitored as delineators of HIV pathogenesis. RESULTS: HIV-2 replication in vitro and in vivo correlated with nascent antigen production and rising viral titers as determined by infectious center assays. Infection was detectable by polymerase chain reaction amplification of proviral sequences in macaque cells as early as 1 week postinoculation. Two distinct patterns of CD4+ cell depletion induced by HIV-2 infection were observed during the first month postinoculation and characterized by a moderate loss sustained through 20 weeks postinoculation or a substantial loss maintained long-term (> 90 weeks). Identity between inoculating viral stocks and subsequent viral isolates from animals was established comparatively by limited sequence analysis of specific domains within the HIV-2 pol and env genes. In contrast, replication of HIV-1 isolates was limited or only semipermissive in vitro. Intravenous inoculation of HIV-1 field isolates, using conditions successful for HIV-2 (for example, identical viral titers), failed to establish a productive viral infection leading to seroconversion of fluctuations in hematologic cell markers. Infection with a high-titer inoculum of a laboratory-adapted HIV-1 strain in vivo, as demonstrated by polymerase chain reaction analysis, produced seroconversion in the absence of overt viral replication or hematologic variations in one out of four animals. CONCLUSIONS: This system provides for multifaceted modeling of HIV pathogenesis, primarily with HIV-2 and potentially with HIV-1/-2 chimerics, in support of immunotherapeutic developments and critical evaluation of intervention practices.

Relationship between plasma phospholipid transfer protein activity and HDL subclasses among patients with low HDL and cardiovascular disease.

Low levels of high density lipoproteins (HDL) are associated with an increased risk for premature cardiovascular disease. The plasma phospholipid transfer protein (PLTP) is believed to play a critical role in lipoprotein metabolism and reverse cholesterol transport by remodeling HDL and facilitating the transport of lipid to the liver. Plasma contains two major HDL subclasses, those containing both apolipoproteins (apo) A-I and A-II, Lp(A-I, A-II), and those containing apo A-I but not A-II, Lp(A-I). To examine the potential relationships between PLTP and lipoproteins, plasma PLTP activity, lipoprotein lipids, HDL subclasses and plasma apolipoproteins were measured in 52 patients with documented cardiovascular disease and low HDL levels. Among the patients, plasma PLTP activity was highly correlated with the percentage of plasma apo A-I in Lp(A-I) (r=0.514, p < 0.001) and with the apo A-I, phospholipid and cholesterol concentration of Lp(A-I) (r=0.499, 0.478, 0.457, respectively, p < 0.001). Plasma PLTP activity was also significantly correlated with plasma apo A-I (r=0.413, p=0.002), HDL cholesterol (r=0.308, p=0.026), and HDL, and HDL3 cholesterol (r=0.284 and 0.276, respectively, p < 0.05), but no significant correlation was observed with Lp(A-I, A-I), plasma cholesterol, triglycerides, or apo B, very low density lipoprotein cholesterol or low density lipoprotein cholesterol. These associations support the hypothesis that PLTP modulates plasma levels of Lp(A-I) particles without significantly affecting the levels of Lp(A-I, A-II) particles.

Ribose facilitates thallium-201 redistribution in patients with coronary artery disease.

To investigate whether i.v. infusion of ribose, an adenine nucleotide precursor, postischemia facilitates thallium-201 (201Tl) redistribution and improves identification of ischemic myocardium in patients with coronary artery disease (CAD), 17 patients underwent two exercise 201Tl stress tests, performed 1-2 wk apart. After immediate postexercise planar imaging, patients received either i.v. ribose (3.3 mg/kg/min x 30 min) or saline as a control. Additional imaging was performed 1 and 4 hr postexercise. Reversible defects were identified by count-profile analysis. Significantly more (nearly twice as many) reversible 201Tl defects were identified on the post-ribose images compared to the post-saline (control) images at both 1 and 4 hr postexercise (p less than 0.001). Quantitative analyses of the coronary arteriogram was available in 13 patients and confirmed that the additional reversible defects were in myocardial regions supplied by stenosed arteries. We conclude that ribose appears to facilitate 201Tl redistribution in patients with CAD and enhances identification of ischemic myocardium.

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)

Importance of endothelial function in mediating the benefits of lipid-lowering therapy.

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.

Percutaneous transluminal coronary angioplasty and subsequent restenosis: quantitative and qualitative methodology for their assessment.

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.

Effects of verapamil on coronary hemodynamic function and vasomobility relative to its mechanism of antianginal action.

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.

Electron-beam tomography coronary calcium scores are superior to Framingham risk variables for predicting the measured proximal stenosis burden.

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.

Coronary artery dilation and hemodynamic responses after isosorbide dinitrate therapy in patients with coronary artery disease.

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)

Usefulness of recanalization to luminal diameter of 0.6 millimeter or more with intracoronary streptokinase during acute myocardial infarction in predicting "normal" perfusion status, continued arterial patency and survival at one year.

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)

Moderate dose, three-drug therapy with niacin, lovastatin, and colestipol to reduce low-density lipoprotein cholesterol <100 mg/dl in patients with hyperlipidemia and coronary artery disease.

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.

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.