John A. Farmer

Association of levels of lipoprotein Lp(a), plasma lipids, and other lipoproteins with coronary artery disease documented by angiography.

In a study of 307 white patients who underwent coronary angiography, the relationship of coronary artery disease (CAD) to plasma levels of lipoprotein Lp(a) and other lipid-lipoprotein variables was examined. Lp(a) resembles low-density lipoprotein (LDL) in several ways, but can be distinguished and quantified by electroimmunoassay. CAD was rated as present or absent and was also represented by a quantitative lesion score derived from estimates of stenosis in four major coronary vessels. Coronary lesion scores significantly correlated with Lp(a), total cholesterol, triglycerides, LDL cholesterol, and high-density lipoprotein (HDL) cholesterol levels by univariate statistical analysis. By multivariate analysis levels of Lp(a) were associated significantly and independently with the presence of CAD (p less than .02), and tended to correlate with lesion scores (p = .06). Among subgroups Lp(a) level was associated with CAD in women of all ages and in men 55 years old or younger. An apparent threshold for coronary risk occurred at Lp(a) lipoprotein mass concentrations of 30 to 40 mg/dl, corresponding to Lp(a) cholesterol concentrations of approximately 10 to 13 mg/dl. Plasma Lp(a) in white patients appears to be a major coronary risk factor with an importance approaching that of the level of LDL or HDL cholesterol.

Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]).

Despite the potential for reduced morbidity and mortality, aggressive intervention against mild to moderate hypercholesterolemia in patients with coronary heart disease (CHD) remains controversial and infrequently practiced. Eligible patients in the 2.5-year Lipoprotein and Coronary Atherosclerosis Study were men and women aged 35 to 75 years with angiographic CHD and mean low-density lipoprotein (LDL) cholesterol of 115 to 190 mg/dl despite diet. Patients (n = 429; 19% women) were randomized to fluvastatin 20 mg twice daily or placebo. One fourth of patients were also assigned open-label adjunctive cholestyramine up to 12 g/day because prerandomization LDL cholesterol remained > or = 160 mg/dl. The primary end point, assessed by quantitative coronary angiography, was within-patient per-lesion change in minimum lumen diameter (MLD) of qualifying lesions. Across 2.5 years, mean LDL cholesterol was reduced by 23.9% in all fluvastatin patients (+/- cholestyramine) (146 to 111 mg/dl) and by 22.5% in the fluvastatin only subgroup (137 to 106 mg/dl). Primary end point analysis (340 patients) showed significantly less lesion progression in all fluvastatin versus all placebo patients, deltaMLD -0.028 versus -0.100 mm (p <0.01), and for fluvastatin alone versus placebo alone, deltaMLD -0.024 versus -0.094 mm (p <0.02). A consistent angiographic benefit with treatment was seen whether baseline LDL cholesterol was above or below 160 or 130 mg/dl. Beneficial trends with treatment were also consistently seen in clinical event rates but were not statistically significant. Thus, lipid lowering by fluvastatin in patients with mildly to moderately elevated LDL cholesterol significantly slowed CHD progression.

Influence of Low HDL on Progression of Coronary Artery Disease and Response to Fluvastatin Therapy

BACKGROUND--Patients with coronary artery disease (CAD) commonly have low HDL cholesterol (HDL-C) and mildly elevated LDL cholesterol (LDL-C), leading to uncertainty as to whether the appropriate goal of therapy should be lowering LDL-C or raising HDL-C. METHODS AND RESULTS--Patients in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) had mildly to moderately elevated LDL-C; many also had low HDL-C, providing an opportunity to compare angiographic progression and the benefits of the HMG-CoA reductase inhibitor fluvastatin in patients with low versus patients with higher HDL-C. Of the 339 patients with biochemical and angiographic data, 68 had baseline HDL-C <0.91 mmol/L (35 mg/dL), mean 0.82+/-0.06 mmol/L (31. 7+/-2.2 mg/dL), versus 1.23+/-0.29 mmol/L (47.4+/-11.2 mg/dL) in patients with baseline HDL-C >/=0.91 mmol/L. Among patients on placebo, those with low HDL-C had significantly more angiographic progression than those with higher HDL-C. Fluvastatin significantly reduced progression among low-HDL-C patients: 0.065+/-0.036 mm versus 0.274+/-0.045 mm in placebo patients (P=0.0004); respective minimum lumen diameter decreases among higher-HDL-C patients were 0. 036+/-0.021 mm and 0.083+/-0.019 mm (P=0.09). The treatment effect of fluvastatin on minimum lumen diameter change was significantly greater among low-HDL-C patients than among higher-HDL-C patients (P=0.01); among low-HDL-C patients, fluvastatin patients had improved event-free survival compared with placebo patients. CONCLUSIONS--Although the predominant lipid-modifying effect of fluvastatin is to decrease LDL-C, patients with low HDL-C received the greatest angiographic and clinical benefit.

Insensitivity of noninvasive tests to detect coronary artery vasculopathy after heart transplant

Obstructive coronary artery vasculopathy can be a major problem after cardiac transplant. The use of noninvasive tests to detect coronary artery vasculopathy was studied in 73 consecutive patients after heart transplant. Angiographically or autopsy-proved coronary artery disease was noted in 19 consecutive patients (26%) followed prospectively for 2.5 +/- 1.3 years (mean +/- standard deviation). Patients underwent yearly surveillance echocardiographic, rest/exercise-gated wall motion, oral dipyridamole thallium, ambulatory electrocardiographic monitor and angiographic studies. Positive test results were defined by decrease in ejection fraction, wall motion abnormality, failure to increase ejection fraction, lack of systolic blood pressure increase, and ischemic ST changes at maximal exercise (or on ambulatory monitor). Wall motion abnormalities and depressed ejection fraction on echocardiography were also abnormal studies as were fixed or reversible perfusion defects on thallium scan. Angiograms were considered positive when 50% luminal narrowing was observed and autopsy coronary artery vasculopathy was defined as cross-sectional coronary obstruction greater than or equal to 70%. No procedure that was examined proved to be a sensitive noninvasive detector of heart transplant coronary artery vasculopathy. All except ambulatory electrocardiographic monitoring had positive predictive values less than 50%. Interestingly, of the techniques evaluated, echocardiography was most sensitive (53%). The poor predictive ability of noninvasive testing in this population may be due to the fact that these tests are designed to detect effects of ischemia rather than coronary obstruction alone. Use of these particular noninvasive modalities routinely after heart transplant to detect coronary artery vasculopathy should be reconsidered because of their low sensitivity and predictive value when used as a surveillance screen.

Comparative tolerability of the HMG-CoA reductase inhibitors.

The availability of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has revolutionised the treatment of lipid abnormalities in patients at risk for the development of coronary atherosclerosis. The relatively widespread experience with HMG-CoA therapy has allowed a clear picture to emerge concerning the relative tolerability of these agents. While HMG-CoA reductase inhibitors have been shown to decrease complications from atherosclerosis and to improve total mortality, concern has been raised as to the long term safety of these agents. They came under close scrutiny in early trials because ocular complications had been seen with older inhibitors of cholesterol synthesis. However, extensive evaluation demonstrated no significant adverse alteration of ophthalmological function by the HMG-CoA reductase inhibitors.Extensive experience with the potential adverse effect of the HMG-CoA reductase inhibitors on hepatic function has accumulated. The effect on hepatic function for the various HMG-CoA reductase inhibitors is roughly dose-related and 1 to 3% of patients experience an increase in hepatic enzyme levels. The majority of liver abnormalities occur within the first 3 months of therapy and require monitoring. Rhabdomyolysis is an uncommon syndrome and occurs in approximately 0.1% of patients who receive HMG-CoA reductase inhibitor monotherapy. However, the incidence is increased when HMG-CoA reductase inhibitors are used in combination with agents that share a common metabolic path.The role of the cytochrome P450 (CYP) enzyme system in drug-drug interactions involving HMG-CoA reductase inhibitors has been extensively studied. Atorvastatin, cerivastatin, lovastatin and simvastatin are predominantly metabolised by the CYP3A4 isozyme. Fluvastatin has several metabolic pathways which involve the CYP enzyme system. Pravastatin is not significantly metabolised by this enzyme and thus has theoretical advantage in combination therapy. The major interactions with HMG-CoA reductase inhibitors in combination therapy involving rhabdomyolysis include fibric acid derivatives, erythromycin, cyclosporin and fluconazole.Additional concern has been raised relative to overzealous lowering of cholesterol which could occur due to the potency of therapy with these agents. Currently, there is no evidence from clinical trials of an increase in cardiovascular or total mortality associated with potent low density lipoprotein reduction. However, a threshold effect had been inferred by retrospective analysis of the Cholesterol and Recurrent Events study utilising pravastatin and the role of aggressive lipid therapy is currently being addressed in several large scale trials.

Intensive Medical Therapy Versus Coronary Angioplasty for Suppression of Myocardial Ischemia in Survivors of Acute Myocardial Infarction A Prospective, Randomized Pilot Study

BACKGROUND Patients who have inducible ischemia after acute myocardial infarction (AMI) generally undergo coronary angiography with the intent to revascularize. Whether this approach is superior to intensive treatment with anti-ischemic medications is unknown. METHODS AND RESULTS We performed a prospective, randomized pilot study comparing intensive medical therapy with coronary angioplasty (PTCA) for suppression of myocardial ischemia in 44 stable survivors of AMI. Myocardial ischemia was quantified with adenosine 201Tl tomography (SPECT) performed 4.5+/-2.9 days after AMI. All patients at baseline had a large total (>/=20%) and ischemic (>/=10%) left ventricular perfusion defect size (PDS). SPECT was repeated at 43+/-26 days after therapy was optimized. The total stress-induced PDS was comparably reduced with medical therapy (from 38+/-13% to 26+/-16%; P<0.0001) and PTCA (from 35+/-12% to 20+/-16%; P<0.0001). The reduction in ischemic PDS was also similar (P=NS) in both groups. Cardiac events occurred in 7 of 44 patients over 12+/-5 months. Patients who remained clinically stable had a greater reduction in ischemic PDS (-13+/-9%) than those who had a recurrent cardiac event (-5+/-7%; P<0.02). Event-free survival was superior in the 24 patients who had a significant (>/=9%) reduction in PDS (96%) compared with those who did not (65%; P=0.009). CONCLUSIONS In this small pilot study, intensive medical therapy and PTCA were comparable at suppressing ischemia in stable patients after AMI. Sequential imaging with adenosine SPECT can track changes in PDS after anti-ischemic therapies and thereby predict subsequent outcome. Corroboration of these preliminary findings in a larger cardiac-event trial is warranted.

Hyperlipidemia after heart transplantation: Report of a 6-year experience, with treatment recommendations

Mean plasma lipid values in 100 patients who survived greater than 3 months after heart transplantation increased significantly at 3 months over pretransplantation values: total cholesterol from 168 +/- 7 to 234 +/- 7 mg/dl, low density lipoprotein (LDL) cholesterol from 111 +/- 6 to 148 +/- 6 mg/dl, high density lipoprotein (HDL) cholesterol from 34 +/- 1 to 47 +/- 1 mg/dl and triglycerides from 107 +/- 6 to 195 +/- 10 mg/dl. There were no significant increases after this time. The LDL cholesterol values reamined greater than or equal to 130 mg/dl in 64% of patients and triglyceride values remained greater than or equal to 200 mg/dl in 41% of patients 6 months after postoperative dietary instructions. Beginning in 1985, select patients whose total cholesterol values remained greater than 300 mg/dl despite 6 months of dietary intervention were treated with lovastatin given alone in a high dose (40 to 80 mg/day) or in combination with another hypolipidemic agent. Four of the five patients so treated developed rhabdomyolysis; two of the four had acute renal failure. Beginning in 1988, a second protocol--lovastatin at 20 mg/day as monotherapy--was used in patients who despite dietary intervention had total cholesterol greater than 240 mg/dl (mean follow-up 13 months). In the 15 patients so treated, mean total cholesterol decreased from 299 +/- 10 mg/dl before treatment with lovastatin to 235 +/- 9 mg/dl during treatment (21% reduction, p less than 0.001) and mean LDL cholesterol was reduced from a baseline value of 190 +/- 10 to 132 +/- 12 mg/dl during treatment (31% reduction, p less than 0.001). In this study, lovastatin at a dose of less than or equal to 20 mg/day as monotherapy was a well tolerated, effective treatment for hyperlipidemia after heart transplantation. It did not result in rhabdomyolysis and required no alteration in immunosuppressive therapy. However, the dose should not exceed 20 mg/day and combination therapy with either gemfibrozil or nicotinic acid should be avoided, even if the target LDL cholesterol value is not reached.

Pleiotropic effects of statins: do they matter?

Treatment with the 3-hydroxy-3-methylglutaryl coenyzme A reductase inhibitors (or statins) reduces the risk for cardiovascular events across a broad spectrum of patient profiles, as evidenced by both primary prevention and secondary prevention trials. Improved survival by way of reduced deaths from coronary heart disease was also reported with these agents, which are primarily indicated for substantial reduction in LDL-cholesterol levels. However, the statins are extremely complex drugs and exhibit a wide variety of vascular effects that may or may not be dependent on their lipid-modifying properties. These so-called pleiotropic effects include alterations of endothelial function, inflammation, coagulation, and plaque stability. The relative contribution of the nonlipid effects of statin therapy to the well-documented clinical benefits is currently under intense investigation.

The implications for cardiac recovery of left ventricular assist device support on myocardial collagen content.

BACKGROUND To define the beneficial cellular changes that occur with chronic ventricular unloading, we determined the effect of left ventricular assist device (LVAD) placement on myocardial fibrosis. METHODS We obtained paired myocardial samples (before and after LVAD implantation) from 10 patients (aged 43 to 64 years) with end-stage cardiomyopathy. We first determined regional collagen expression of an explanted heart by a computerized semiquantitative analysis of positive picro-sirius red stained areas. RESULTS We found that there was no statistically significant difference in collagen content between regions of the failed heart studied. Next we determined collagen content in these paired myocardial biopsies pre- and post-LVAD implantation. All 10 patients had significant reductions in collagen content after LVAD placement with a mean reduction of 82% (percent of tissue area stained decreased from 32% +/- 4% to 4% +/- 0.8%, P < 0.001). CONCLUSION In summary, these data demonstrate that chronic mechanical circulatory support significantly reduces fibrosis in the failing myocardium.

Effects of lipid lowering therapy on progression of coronary and carotid artery disease.

Recent data have extended the benefit of lipid lowering therapy to patients with only mildly to moderately elevated LDL-cholesterol, which is typical of patients with coronary artery disease. Meta-analysis of clinical trials of statin therapy with similar sample sizes indicated that the LDL-cholesterol level on treatment was as good a predictor of angiographic benefit as was the percentage reduction in LDL-cholesterol. We review evidence that management of triglyceride-rich lipoproteins, HDL, fibrinogen, lipoprotein particle size, LDL-oxidation, and lipoprotein (a) may also favorably influence atherosclerotic progression. Angiographic and arterial ultrasound trials of lipid lowering therapy have demonstrated benefits on disease progression that are consistent with benefits on myocardial infarction, stroke, and death reported in larger, lengthier trials.