Novel anti-platelet agents for the treatment of stable angina pectoris.

Antiplatelet treatment is an important element in the medical treatment of patients with stable angina. Single antiplatelet therapy with low-dose aspirin is recommended in the absence of contraindications in all patients with diagnosed chronic stable angina and ischemic heart disease. Dual antiplatelet therapy is recommended initially for all patients with stable angina undergoing elective angioplasty with the duration of P2Y12 antagonist administration depending on the type of coronary stent. Despite the demonstrated clinical benefit in a wide range of patients, residual risk of ischemic events with aspirin and a P2Y12 inhibitor has also been attributed to the fact that these agents do not inhibit all pathways involved in platelet activation and aggregation. Other platelet activation pathways, including the PAR-1 pathway activated by thrombin (the most potent platelet activator), remain active in the presence of current antiplatelet agents. A combination of current therapies with novel agents could provide more comprehensive platelet inhibition leading to incremental decrease of cardiovascular events at the expense of increased bleeding risk. The current review presents traditional and novel antiplatelet treatment options and discusses the indications for aggressive antiplatelet management in patients with stable angina pectoris.

The activation of endothelin-1 pathway during methionine-induced homocysteinemia mediates endothelial dysfunction in hypertensive individuals.

OBJECTIVES: Endothelin-1 (ET-1) is a key regulator of arterial blood pressure in humans, and homocysteinemia is associated with increased oxidative stress. It is still unclear whether homocysteine-induced oxidative stress is implicated in the regulation of ET-1 expression. We examined the impact of acute homocysteinemia on endothelial function in hypertensive patients and healthy individuals, and the potential role of ET-1. METHODS: In this double-blind, placebo-controlled study, 39 hypertensive and 49 healthy individuals were randomized to receive high-dose vitamins (2 g vitamin C and 800IU vitamin E) or placebo followed by methionine loading 100 mg/kg body weight. Endothelium-dependent dilation (EDD) and endothelium-independent dilation (EID) of the brachial artery were evaluated by plethysmography, at baseline and 4 h postloading (4 h PML). ET-1 was measured by ELISA, whereas total lipid hydroperoxides (per-ox) levels were measured by a commercially available photometric technique. RESULTS: Acute, methionine-induced homocysteinemia decreased EDD in all study groups (P < 0.001 for all), whereas vitamins pretreatment failed to prevent this effect, despite the vitamins-induced reduction of peroxidation in the hypertensives group (P < 0.05). On the contrary, methionine loading significantly increased plasma ET-1 levels only in hypertensives (P < 0.05), an effect which was not prevented by antioxidant vitamins (P < 0.05). EID remained unchanged after methionine loading, in all study groups (P = NS for all groups). CONCLUSION: Experimental homocysteinemia rapidly blunts endothelial function in both hypertensive individuals and healthy individuals. The rapid elevation of ET-1 levels observed only in hypertensives, suggests that ET-1 may be the key mediator of homocysteine-induced endothelial dysfunction, independently of oxidative stress.

Alternative splicing generates a CaM kinase IIbeta isoform in myocardium that targets the sarcoplasmic reticulum through a putative alphaKAP and regulates GAPDH.

We report the isolation of a full length cDNA from cardiac muscle that encodes a approximately 73 kDa calcium/calmodulin (CaM) dependent kinase IIbeta isoform (CaMKIIbeta(C)) that was generated by alternative splicing of the CaMKIIbeta gene. Antipeptide antibodies raised to specific regions of the kinase identified a 73 kDa kinase polypeptide in cardiac SR. Anti-alpha kinase anchoring protein (alphaKAP) antibodies identified a 25 kDa polypeptide in cardiac SR and RT-PCR followed by sequence analysis confirmed the presence of a full length alphaKAP encoding transcript in myocardium. Protein interaction assays revealed that the 73 kDa CaMKIIbeta(C) binds GAPDH to modulate the production of NADH in a Ca2+/CaM dependent reaction. The presence of a CaMKIIbeta isoform that can target the SR presumably via its membrane anchor alphaKAP defines a previously unrecognized Ca2+/CaM regulatory system in myocardium.