Revascularization in the high-risk patient: multivessel disease

The aim of this article is to review the treatment of patients with multi-vessel coronary artery disease. Percutaneous coronary intervention (PCI) has been challenging coronary artery bypass grafting (CABG) as the gold standard of care for patients with multi-vessel disease; however, the application of PCI to these patients has been mainly limited by restenosis. Up to the late 1990s, numerous large-scale, randomized trials addressed this issue comparing CABG to PCI with balloon angioplasty or bare-metal stents. These studies demonstrated similar rates of death and myocardial infarction in both groups, while the need for revascularization remained significantly lower in the CABG group. Drug-eluting stents (DES) have dramatically reduced restenosis and repeat revascularization rates. CABG has also progressed with improvements in perioperative management, a higher use of arterial grafting, and advanced techniques with the implementation of minimally invasive and off-pump surgery as options. Therefore, the results of previous trials in the pre-DES era can no longer be extrapolated into the 'real world'. As intermediate steps preceding a fully-fledged, randomized trial, several trials have compared PCI with DES and the historical control of CABG, but the results are still inconclusive. Several dedicated randomized trials are currently ongoing to compare PCI with DES and CABG using contemporary techniques. Until the results of these randomized trials are presented, the choice for each strategy should be based on the patients' individual risk and anatomy.     

Improvement of cardiac function with parecoxib, a cyclo-oxygenase-2 inhibitor, in a rat model of ischemic heart failure

OBJECTIVE: To assess changes in cardiac function in animals with ischemic congestive heart failure (CHF) treated with a selective cyclo-oxygenase-2 (COX-2) inhibitor. BACKGROUND: In patients with CHF, COX-2 expression was associated with features of worsening failure. However, evidence of beneficial or detrimental functional effects of COX-2 inhibition in ischemic CHF is lacking. METHODS: Thirty male Wistar rats underwent coronary ligation and were allowed to recover for 12 months. Five sham-operated animals were used as controls. After 12 months, six surviving animals underwent baseline echocardiogram to measure end-diastolic diameter (EDD), end-systolic diameters (ESD), fractional shortening (FS), and anterior and posterior diastolic and systolic wall thicknesses. The animals were thereafter treated by daily intraperitoneal parecoxib injections (0.75 mg/kg) for 7 days. On day 7, a repeat echocardiogram was performed. RESULTS: When compared to baseline, repeat echocardiography after 7 days of parecoxib treatment showed no changes in the EDD (9.4 +/- 0.4 mm vs. 9.4 +/- 0.3 mm, P = 0.9), a significant reduction of ESD (5.5 +/- 0.8 mm vs. 6.4 +/- 0.3 mm, P = 0.028), and a significant improvement in the FS (43 +/- 3% vs. 32 +/- 5%, P = 0.027). Improvement of FS was associated with a significant change in systolic thickness in the infarct zone (3.6 +/- 0.4 mm vs. 3.0 +/- 0.1 mm, P = 0.046), whereas no significant changes in systolic thickness in the remote area were observed. CONCLUSIONS: Administration of parecoxib in ischemic CHF provides functional improvement of the peri-infarct myocardium. This finding may prove useful in improving quality of life and, perhaps, survival in patients with ischemic heart disease.     

Determinants of 25-hydroxyvitamin D levels in African-American and Caucasian male veterans

Summary  

Among 307 males seen in VA Medical Center, independent determinants (p < 0.01 for all) of serum 25-hydroxyvitamin D [25(OH)D] levels included race, vitamin D supplements, BMI, dietary calcium intake and smoking, but not age. Negative association between 25(OH)D and parathyroid hormone (PTH) was similar for Caucasian and African-American men.     

Pharmacological preconditioning with sildenafil: Basic mechanisms and clinical implications

The phosphodiesterase type-5 (PDE5) inhibitor, sildenafil, is the first drug developed for treatment of erectile dysfunction in patients. Experimental data in animals show that sildenafil has a preconditioning-like cardioprotective effect against ischemia/reperfusion injury in the intact heart. Mechanistic studies suggest that sildenafil exerts cardioprotection through NO generated from eNOS/iNOS, activation of protein kinase C/ERK signaling and opening of mitochondrial ATP-sensitive potassium channels. Additional studies show that the drug attenuates cell death resulting from necrosis and apoptosis, and increases the Bcl2/Bax ratio through NO signaling in adult cardiomyocytes. Emerging new data also suggest that sildenafil may be used clinically for treatment of pulmonary arterial hypertension and endothelial dysfunction. Future demonstration of the cardioprotective effect in patients with the relatively safe and effective FDA-approved PDE5 inhibitors such as sildenafil could have an enormous impact on bringing the long-studied phenomenon of ischemic and pharmacologic preconditioning to the clinical forefront.     

NKT cells and type-1 diabetes and the "hygiene hypothesis" to explain the rising incidence rates

Immune-mediated (type-1) diabetes (IMD) is a multigenetic disease that is strongly influenced by the environment. Whereas the incidence rates are steadily rising worldwide, less than half of affected identical twins ever become concordant for IMD or even beta-cell autoimmunity. Worldwide, it is the tropical regions of the world that are replete in infectious and parasitic diseases that are the least affected. Repeated efforts to identify the putative inductive agents for beta-cell autoimmunity have proved unrewarding. Rather, we suggest that some environments are less protective than others and argue that it is the fall in incidences of infectious diseases and intestinal parasites that are likely responsible for the rise in autoimmune diseases like IMD in the West. Nonobese diabetic (NOD) mice reared in gnotobiotic environments have only worsened diabetes, while recent studies suggest that multiple defects in immune tolerance to self must be present before IMD can develop in the human or mouse. We speculate herein that the deficiency in natural killer T (NKT) cells in IMD in both species may be both genetic and environmentally influenced, predisposing to pancreatic beta-cell autoimmunity through a dysfunction of immunoregulatory T cells, with defective peripheral control of islet cell protein autoreactive cytotoxic CD8+ T cells. The encouraging results in NOD mice using alpha-galactosylceramide to stimulate NKT cells now warrant trials with this and other glycolipid NKT cell-stimulating agents in humans. Since it has become apparent that autoimmune diseases such as IMD are the result of an underlying immunodeficiency state, we strongly argue that its effective prevention will likely come through the use of immunostimulation and not through side effect-prone immunosuppression.     

Alpha-adrenergic receptor stimulation produces late preconditioning through inducible nitric oxide synthase in mouse heart

Inducible nitric oxide synthase (iNOS) mediates late preconditioning (PC) induced by ischemia and pharmacological agents. Since alpha -adrenoceptor (alpha -AR) stimulation is one of the key triggers of PC, we hypothesized that activation of this receptor may induce delayed cardioprotective effect via iNOS-sensitive mechanisms. Adult male ICR mice were treated i.p. with either vehicle/inhibitors or phenylephrine (10 mg/kg) and subjected to 30 min of global ischemia and 30 min reperfusion in Langendorff mode 24 h later. 5-Methyl-urapidil (3 mg/kg) and chloroethylclonidine (3 mg/kg) were injected 15 min prior to phenylephrine to block alpha -AR(1A) and alpha -AR(1B) receptors respectively. S-Methylisothiourea (3 mg/kg), an iNOS inhibitor, was given 60 min prior to ischemia in phenylephrine-pretreated mice. Preischemic NO(x) was measured using a chemoluminescence reaction. Phenylephrine treatment reduced infarct size from 31.10 +/- 0.79% (vehicle) to 14.24 +/- 0.84% (P<0.001). Chloroethylclonidine blocked the effect of phenylephrine (infarct size 31.31 +/- 1.69%) but 5-methyl-urapidil (17.72 +/- 1.25%) did not. Phenylephrine-induced delayed cardioprotection was abolished by S-methylisothiourea and absent in iNOS knockout mice. Baseline NO(x) content was significantly increased in phenylephrine and 5-methyl-urapidil+phenylephrine treated hearts, but remained at baseline levels in hearts treated with chloroethylclonidine, 5-methyl-urapidil or S-methylisothiourea. Western blot analysis revealed a 1.8-fold increase in iNOS with phenylephrine, which was inhibited by chloroethylclonidine but not by 5-methyl-urapidil. We conclude that phenylephrine-induced delayed PC is mediated by selective activation of alpha-AR(1B). Enhanced iNOS expression concomitant with increased NO synthesis, as well as pharmacological blockade and absence of cardioprotection in iNOS knockout mice suggests an essential role of NO in phenylephrine triggered late PC.     

Development of skeletal metastasis by human prostate cancer in athymic nude mice

The biology of skeletal metastasis is poorly understood. In order to establish an animal model of bone metastasis, cells from a human prostate cancer cell line (PC-3) were injected into the tail veins of athymic nude mice while the inferior vena cava was occluded. This technique was used in order to divert cells into the vertebral venous plexus. A control group of animals received tumor cells without caval occlusion. Bone lesions developed in 3/16 (19 per cent) experimental mice and in none of the control mice. The incidence of lung metastasis was significantly decreased in the experimental mice (5/16) as compared with non-occluded control mice (14/16). Two tumor sublines were established from explant cultures of bone lesions. Injection of these cells resulted in bone metastasis in 19/36 (53 per cent) mice (P=0.03 compared with the parent line). The incidence of lung lesions was also increased. The predominant site of bone metastasis was the lumbar vertebrae; other affected sites were the pelvis and femurs. All bone lesions resulted in extensive bone destruction. The successful development of bone metastasis using the technique of caval occlusion lends support to the hypothesis that entry of cells into the vertebral circulation is an important step in the development of these lesions. This model should be of value in understanding the pathogenesis of bone metastasis, and in studying the effects of various agents on the prevention and control of these lesions.