BackgroundProprotein convertase subtilisin kexin-like 9 (PCSK9) is a secreted glycoprotein that is transcriptionally regulated by cholesterol status. It modulates levels of circulating low density lipoprotein cholesterol (LDLC) by negatively regulating low density lipoprotein receptor (LDLR) levels. PCSK9 variants that result in 'gain of function' have been linked to autosomal dominant hypercholesterolemia, while significant protection from coronary artery disease has been documented in individuals who carry 'loss of function' PCSK9 variants. PCSK9 circulates in human plasma, and we previously reported that plasma PCSK9 is positively correlated with total cholesterol and LDLC in men.ResultsHerein, we report the effects of two lipid-modulating therapies, namely statins and fibrates, on PCSK9 plasma levels in human subjects. We also document their effects on endogenous PCSK9 and LDLR expression in a human hepatocyte cell line, HepG2, using immunoprecipitation and immunoblot analyses. Changes in plasma PCSK9 following fenofibrate or gemfibrozil treatments (fibric acid derivatives) were inversely correlated with changes in LDLC levels (r = -0.558, p = 0.013). Atorvastatin administration (HMGCoA reductase inhibitor) significantly increased plasma PCSK9 (7.40%, p = 0.033) and these changes were inversely correlated with changes in LDLC levels (r = -0.393, p = 0.012). Immunoblot analyses of endogenous PCSK9 and LDLR expression by HepG2 cells in response to statins and fibrates showed that LDLR is more upregulated than PCSK9 by simvastatin (2.6× vs 1.5×, respectively at 10 μM), while fenofibrate did not induce changes in either.ConclusionThese results suggest that in vivo (1) statins directly increase PCSK9 expression while (2) fibrates affect PCSK9 expression indirectly through its modulation of cholesterol levels and (3) that these therapies could be improved by combination with a PCSK9 inhibitor, constituting a novel hypercholesterolemic therapy, since PCSK9 was significantly upregulated by both treatments.

We studied the development of tolerance to isosorbide dinitrate in 12 patients with chronic stable angina pectoris. The effect of 30 mg of isosorbide dinitrate on treadmill exercise performance was assessed before and at one, three, and five hours after a single dose. As compared with placebo, the drug increased treadmill walking time until the onset of angina and until the development of moderate angina over the five-hour observation period (P less than 0.05). The patients then received 30 mg of isosorbide dinitrate twice, three times, and four times daily for a period of one week, and exercise performance was assessed before and at one, three, and five hours after the final morning dose. During sustained treatment two and three times daily, treadmill walking time was longer throughout the five-hour testing period than during the placebo phase (P less than 0.05). In contrast, during treatment four times daily, treadmill walking time was prolonged at one hour (P less than 0.05) but not at three and five hours after the last dose. We conclude that tolerance to the clinical effects of isosorbide dinitrate develops with a sustained dosage of 30 mg four times daily, but not when the drug is given two or three times daily.

The hemodynamic and antianginal effects of 30 mg of isosorbide dinitrate (ISDN) were assessed in 12 patients with chronic stable angina after initial dosing and after 7 to 10 days of therapy four times daily. During early therapy, ISDN produced significant hemodynamic and antianginal effects that persisted over a 3 hr observation period. During sustained therapy there was attenuation of the hemodynamic effects at rest, and treadmill exercise time to the onset of angina and to the development of moderate angina was increased 1 hr after dosing; no effect was apparent at 3 hr. During this state of nitrate tolerance, patients were treated with an infusion of normal saline or 100 mg/kg N-acetylcysteine and exercise testing was repeated. N-Acetylcysteine did not change the hemodynamic findings at rest or during exercise and there was no improvement in exercise tolerance. It is apparent that the short-term administration of reduced sulfhydryl groups does not reverse tolerance to the hemodynamic and antianginal effects of isosorbide dinitrate in an exercise test model. Circulation 76, No. 3, 572-576, 1987. IT HAS BEEN RECOGNIZED for many years that the administration of organic nitrates is associated with the rapid development of tolerance. This has been demonstrated in experimental animals, in which continued nitrate administration led to diminished hypotensive effects and increasing amounts of nitrates could be administered over short periods of time with greatly reduced hemodynamic effects. " 2 Tolerance has also been demonstrated in munitions workers3 and in patients treated with organic nitrates for angina pectoris-9 and left ventricular failure.'0 "The most widely accepted theory for the mechanism of tolerance is that during continued nitrate exposure there is a deficiency of reduced sulfhydryl groups in vascular smooth muscle. 12,13 This leads to diminished S-nitrosothiol and cyclic guanosine monophosphate production. The latter is considered responsible for nitrate-induced vasodilatation. Other explanations include plasma volume expansion'4 and augmented neurohumoral responses with activation of the renin angiotensin system,'5 changes that could modify the vasodilator effect of the nitrates.This study was designed to test the hypothesis that deficiency of reduced sulfhydryl groups during nitrate therapy is responsible for the development of tolerance and that the administration of sulfhydryl groups will reverse tolerance. MethodsTwelve patients with chronic, stable angina pectoris entered and completed this invetigation. Coronary artery disease was documented by previous myocardial infarction or arteriographic evidence of significant coronary artery disease (>75% narrowing of at least one major coronary artery). Patients also experienced typical exertional angina and had positive treadmill tests as defined by the development of chest pain during exercise testing with the appearance of ischemic ST segment depression (horizontal or downsloping ST segment depression of at least 1 mm for 80 msec after t...

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This multicenter, double-blind, placebo-controlled study compares the effects of captopril treatment with those of digoxin treatment during maintenance diuretic therapy in patients with mild to moderate heart failure. Compared with placebo, captopril therapy resulted in significantly improved exercise time (mean increase, 82 s vs 35 s) and improved New York Heart Association class (41% vs 22%), but digoxin therapy did not. Digoxin treatment increased ejection fraction (4.4% increase) compared with captopril therapy (1.8% increase) and placebo (0.9% increase). The number of ventricular premature beats decreased 45% in the captopril group and increased 4% in the digoxin group in patients with more than ten ventricular premature beats per hour. Treatment failures, increased