Diagnostic Clues in Cardiovascular Disease

Sophisticated instrumentation and specialized procedures have not entirely replaced careful physical examination in diagnosing cardiovascular disease. Bedside findings have been scientifically correlated with disease states, and the physician's eyes and fingertips are again classified among the more important instruments for detecting the first clues to cardiovascular disease.     

NIACIN AND MYOCARDIAL METABOLISM

Niacin given intravenously inhibits the use of free fatty acids as energy substrate by human myocardial tissue. Because of this, cardiac tissue extracts more carbohydrate substrate from the blood and depletes its reserve of glycogen and endogenous lipid.     

Optical coherence tomography findings in niacin maculopathy

CASE REPORT: We present the case of 54-year-old male who developed bilateral cystoid macular thickening while taking 3 g of niacin per day, and we describe the optical coherence tomography (OCT) features of niacin (nicotinic acid) maculopathy. COMMENTS: Cystoid spaces were seen in both the outer plexiform and inner nuclear layers of both eyes. The cystoid spaces were largest and central in the outer plexiform layer, whereas a broader distribution of smaller cysts was seen in the inner nuclear layer. With cessation of niacin, his vision improved and the OCT features normalized.     

Pellagra in a woman using alternative remedies

A young woman presented with pellagra. Dietary intake of niacin was in excess of recommended guidelines. She had a low body mass index and was taking a number of alternative remedies. Resolution was rapid with oral nicotinic acid and discontinuation of the remedies.     

Aromatic D-amino acids act as chemoattractant factors for human leukocytes through a G protein-coupled receptor,GPR109B

GPR109B (HM74) is a putative G protein-coupled receptor (GPCR) whose cognate ligands have yet to be characterized. GPR109B shows a high degree of sequence similarity to GPR109A, another GPCR that was identified as a high-affinity nicotinic acid (niacin) receptor. However, the affinity of nicotinic acid to GPR109B is very low. In this study, we found that certain aromatic D-amino acids, including D-phenylalanine, D-tryptophan, and the metabolite of the latter, D-kynurenine, decreased the activity of adenylate cyclase in cells transfected with GPR109B cDNA through activation of pertussis toxin (PTX)-sensitive G proteins. These D-amino acids also elicited a transient rise of intracellular Ca²⁺ level in cells expressing GPR109B in a PTX-sensitive manner. In contrast, these D-amino acids did not show any effects on cells expressing GPR109A. We found that the GPR109B mRNA is abundantly expressed in human neutrophils. D-phenylalanine and D-tryptophan induced a transient increase of intracellular Ca²⁺ level and a reduction of cAMP levels in human neutrophils. Furthermore, knockdown of GPR109B by RNA interference inhibited the D-amino acids-induced decrease of cellular cAMP levels in human neutrophils. These D-amino acids induced chemotactic activity of freshly prepared human neutrophils. We also found that D-phenylalanine and D-tryptophan induced chemotactic responses in Jurkat cells transfected with the GPR109B cDNA but not in mock-transfected Jurkat cells. These results suggest that these aromatic D-amino acids elicit a chemotactic response in human neutrophils via activation of GPR109B.     

Nicotinic acid: clinical considerations

Introduction: Nicotinic acid (NA), the oldest hypolipidemic drug, possesses unique broad-spectrum beneficial effects on lipid profiles. Specifically, NA reduces both triglycerides and low-density lipoprotein cholesterol levels, while significantly increasing high-density lipoprotein cholesterol levels. However, NA is often avoided in the clinical setting, or prematurely discontinued by the provider or patient, due to side effects that could possibly be prevented (flushing, gastrointestinal disorders) or that are feared out of proportion to their true incidence rate (hyperglycemia, hyperuricemia).

Areas covered: This article reviews NA's side effects, along with a number of old and new strategies to reduce their incidence, especially flushing. The aim of this paper is to provide a useful clinical guide to the administration of NA in dyslipidemic patients.

Expert opinion: An important number of side effects affects compliance and restricts NA's clinical use. NA-induced flushing is the most restricting side effect, accounting for the majority of NA therapy discontinuations. In addition, gastrointestinal side effects, hyperuricemia, deterioration of glycemic profile, or even new-onset diabetes discourage therapy consecution. Aspirin pretreatment, considered selection and proper counseling of patients, and regular monitoring of liver aminotransferases, creatine kinase, serum uric acid levels, and glycemic profiles can reduce NA's side effect rate and improve compliance.     

Lipid-lowering effects of statins: a comparative review

The pharmacological regulation of lipid metabolism in patients with dyslipidaemia is unequivocally associated with significant reductions in risk for cardiovascular morbidity and mortality. There is strong clinical trial data to support of the use of statin therapies in the settings of both primary and secondary prevention. This paper addresses: i) the mechanisms of action of antilipidaemic medications; ii) dosing regimens and the pharmacokinetic differences among drugs of the same class; iii) risk for drug interactions; and iv) reviews the clinical trial evidence used to support the use of particular antilipidaemic medications in specific physiological settings.     

The continuing complexities of high-density lipoprotein metabolism in drug discovery and development

The termination of the Phase III clinical trial of Pfizer's CETP inhibitor torcetrapib, Investigation of lipid level management to understand its impact in atherosclerotic events (ILLUMINATE), due to excess mortality in the treatment group raised many questions for those involved in the discovery and development of drugs targeting high-density lipoprotein and of atherosclerosis in general. Although the reasons for the failure of torcetrapib are still not known, some of the consequences for the wider field are already apparent. Several imaging studies with torcetrapib showed no change in the various measures of lesion size, which gave some confidence in the interpretation of such studies. Although the case for raising high-density lipoprotein is strong and widely accepted, there will be a much closer interrogation of drugs targeting new mechanisms that will result in longer development times. In the meantime, existing drugs which modify high-density lipoprotein are being revisited, particularly niacin. This editorial commentary briefly discusses these and related issues from the perspective of 6 months following the termination of ILLUMINATE.     

Current and emerging paradigms in the therapeutic management of atherosclerosis

Background: The pathogenesis of atherosclerosis lies in abnormalities in lipoprotein metabolism leading to pathological interactions with vessel walls and the release of inflammatory components, which further aggravate the disease condition. Objective: To elucidate current and emerging trends in drug discovery towards the development of new entities regulating lipoprotein metabolism and inflammatory components to combat the progression of atherosclerosis. Methods: Research/review articles in the public domain and press releases were employed. Results/conclusion: With the recent failure of torcetrapib and succinobucol, drug discovery and development efforts towards the treatment of atherosclerosis have received a big jolt and have been slowed down to certain extent. But this could be a starting point for several new mechanisms that are emerging to discover new drugs to combat the disease.