Effect of the alpha-adrenergic blocker, doxazosin, on endothelial function and insulin action

Essential hypertension is associated with impairment of both endothelial function and insulin action, and this has provided rationale for the use of antihypertensive agents that are at least neutral, if not beneficial, in these areas. This study examines the effect of the alpha-adrenergic blocker, doxazosin, on endothelial function and insulin action. Sixteen patients with essential hypertension were recruited with 13 (3 men/10 women; median age, 55 years; range, 38 to 65 years) completing the study. A double-blind, placebo-controlled crossover study design was used. After a 6-week placebo run-in, there were two 12-week treatment periods of either placebo or doxazosin, separated by a 6-week wash out period. Subjects were studied at the end of each treatment period with endothelial function assessed by forearm plethysmography and insulin action by the hyperinsulinemic clamp technique. Blood pressure was significantly lowered by doxazosin (doxazosin 144 +/-3/86 +/- 2 mm Hg; placebo 159 +/- 3/96 +/- 1 mm Hg, P <.005 for both systolic and diastolic pressure; mean +/- SEM). Baseline forearm blood flow (FBF) was unchanged (doxazosin 4.9 +/- 0.9; placebo 4.0 +/- 0.7 mL x 100 mL(-1) x min(-1), P >.05), however, FBF responses (area under dose response curve, percentage change in infused:control arm ratio) to acetylcholine (endothelium-dependent vasodilation) were improved by doxazosin (doxazosin 58.6 +/- 11.7 standard units [SU]; placebo 22.1 +/- 7.0 SU, P =.03) with responses to sodium nitroprusside (endothelium-independent vasodilation) unchanged (doxazosin 40.3 +/- 5.5 SU; placebo 46.3 +/- 8.1 SU, P >.05). Exogenous glucose infusion rates to maintain euglycemia during hyperinsulinemia were not significantly different (doxazosin 30.4 +/- 0.9; placebo 32.3 +/- 1.0 micromol x kg(-1) min(-1), P >.05). Suppression of postabsorptive endogenous glucose production by insulin was also unchanged by treatment (doxazosin 65.6% +/- 7.5% suppression; placebo 68.3% +/- 11.2% suppression, P >.05). Doxazosin has a neutral effect on both peripheral and hepatic insulin action, but improves endothelium-dependent vasodilation. These results indicate that doxazosin can be used safely in patients with insulin resistance, while its positive effect on endothelial function may lessen the subsequent incidence of atherosclerosis.     

Accuracy in precordial ECG lead placement: Improving performance through a peer-led educational intervention

Background and objectives

Inaccurate electrocardiography (ECG) lead placement may lead to erroneous diagnoses, such as poor R wave progression. We sought to assess the accuracy of precordial ECG lead placement amongst hospital staff members, and to re-evaluate performance after an educational intervention.

Effects of percutaneous transluminal septal myocardial ablation for obstructive hypertrophic cardiomyopathy on systolic and diastolic left ventricular function assessed by pressure-volume loops

The aim of the present study was to determine the long-term effects of percutaneous transluminal septal myocardial ablation (PTSMA) on systolic and diastolic left ventricular (LV) functions in patients with obstructive hypertrophic cardiomyopathy (HC). Ten consecutive patients with symptomatic HC despite optimal medical treatment were referred for PTSMA at our center. LV systolic and diastolic functions were assessed by online LV pressure-volume loops obtained by conductance catheter at baseline and at 6 months after the procedure. At follow-up, the mean gradients at rest and after extrasystole were significantly decreased compared with baseline (88 +/- 29 to 21 +/- 11 mm Hg and 130 +/- 50 to 35 +/- 22 mm Hg, respectively, p <0.01 for the 2 comparisons). End-systolic and end-diastolic pressures significantly decreased (p <0.01), whereas end-systolic and end-diastolic LV volumes significantly increased (p <0.01 for the 2 comparisons). Cardiac output and stroke volume were unchanged, as were ejection fraction (p = 0.25) and maximum dP/dt (p = 0.13). The slope of the end-systolic pressure-volume relation was not decreased, indicating a preserved contractility. The relaxation constant time, end-diastolic stiffness, projected volume of the end-diastolic pressure-volume relation at 30 mm Hg, and diastolic stiffness constant showed a significant improvement of active and passive myocardial diastolic properties. In conclusion, PTSMA is an effective method in the treatment of symptomatic patients with HC. At 6-month follow-up, the LV-aortic gradient was decreased and active and passive LV diastolic properties were increased. Myocardial contractility was not decreased and general hemodynamics was maintained.     

Central projections of photoreceptor axons originating from ectopic eyes in Drosophila

Ectopic expression of the retinal determination gene eyeless (ey) induces the formation of supernumerary eyes on antennae, legs, wings, and halteres. These ectopic eyes form ommatidia that contain photoreceptors and accessory cells and respond to light. Here, we demonstrate that ectopic eyes on antennae and legs extend axonal projections to the central nervous system. Furthermore, electroretinograms and morphological evidence indicate that the photoreceptor axons of at least the antennal ectopic eyes can form completely constituted ectopic synapses with foreign postsynaptic elements and suggest that transmission at these sites may be functional. However, the ectopic axons do not connect to their correct optic lobe targets and do not project deeply into the neuropile, but rather form synapses at superficial positions in the neuropils. By means of confocal and electron microscopy we show that these ectopic synapses resemble normal synapses, albeit with some distinct morphological differences. Our data strongly suggest that the developmental programs controlling photoreceptor synaptogenesis and visual map formation depend to a considerable extent on presynaptic and thus photoreceptor-autonomous steps. Our data also suggest that photoreceptor axon projections and the establishment of the highly stereotypical neural circuitry in the optic lobe, the normal target neuropil, may depend on target-specific cues that appear to be absent from the antennal lobe and thoracic ganglion.     

Anti-platelet antibodies in patients with systemic lupus erythematosus and the primary antiphospholipid antibody syndrome: their relationship with the observed thrombocytopenia

The role of antiphospholipid antibodies in the pathogenesis of the thrombocytopenia observed during primary antiphospholipid antibody syndrome (APAS) and systemic lupus erythematosus (SLE) remains controversial. We have used the MAIPA test to examine the frequency and specificity of anti-platelet antibodies directed against the major platelet membrane glycoproteins (GP IIb–IIIa, GP Ib–IX, GP Ia–IIa and GP IV) in patients where SLE and APAS were associated or not with thrombocytopenia. Results were compared with a series of 26 ITP patients, 46% of whom were shown to possess anti-platelet antibodies directed against one or more of the platelet surface glycoproteins. When APAS was associated with thrombocytopenia, 7/10 patients possessed antibodies against GP IIb–IIIa and/or GP Ib–IX. For SLE patients with thrombocytopenia, 6/10 patients were shown to have antiplatelet antibodies against GP IIb–IIIa, GP Ib–IX or GP IV. In contrast, for APAS ( n =11) and SLE patients ( n =11) without thrombocytopenia, only one patient had an antibody directed against GP IIb–IIIa and one patient had an antibody to GP IV. Our results suggest that antibodies directed against major platelet membrane glycoproteins may play a role in the thrombocytopenia that is seen during SLE and APAS.     

Enhanced atherogenesis is not an obligatory response to systemic herpesvirus infection in the apoE-deficient mouse: comparison of murine gamma-herpesvirus-68 and herpes simplex virus-1

Viral and bacterial infectious agents have been implicated in the etiology of atherosclerosis. We have previously shown that a gamma-herpesvirus can accelerate atherosclerosis in the apolipoprotein E-deficient (apoE-/-) mouse. To address whether a virally induced systemic immune response is sufficient to trigger enhanced atheroma formation, we infected apoE-/- mice with murine gamma-herpesvirus-68 (MHV-68) or herpes simplex virus-1 (HSV-1). In this study, we show that both viruses were able to induce a cell-mediated and humoral immune response in the apoE-/- mouse, which was sustained over a period of 24 weeks. Although intranasal or intraperitoneal infection with MHV-68 induced similar levels of virus-specific IgG1 and IgG2a antibodies in the serum of apoE-/- mice, those infected with HSV-1 showed higher anti-HSV-1 IgG2a compared with IgG1 antibody levels. In addition, viral message was not detected in the aortas of HSV-1-infected animals, whereas we have shown previously that MHV-68 mRNA can be detected in the aortas of infected mice as early as 5 days after infection. Compared with control mice, apoE-/- mice infected with MHV-68 showed accelerated atherosclerosis, whereas mice infected with HSV-1 did not. These data indicate that a systemic immune response to any particular infectious agent is insufficient to induce enhanced atherosclerosis in the apoE-/- mouse and point to specific infections or immune mechanisms that might be essential for virally enhanced atherogenesis.     

Novel approach to discriminate left bundle branch block from nonspecific intraventricular conduction delay using pacing-induced functional left bundle branch block

Purpose

Left bundle branch block (LBBB) has a predictive value for response to cardiac resynchronization therapy as reported by Zareba et al. (Circulation 123(10):1061–1072, 2011). However, based on ECG criteria, the discrimination between complete LBBB and nonspecific intraventricular conduction delay is challenging. We tested the hypothesis that discrimination can be performed using standard electrophysiological catheters and a simple stimulation protocol.

Methods

Fifty-nine patients were analyzed retrospectively. Patients were divided into groups of narrow QRS (n?=?20), wide QRS of right bundle branch block (RBBB) morphology (n?=?14), and wide QRS of LBBB morphology (n?=?25). Using a diagnostic catheter placed in the coronary sinus, left ventricular activation was assessed during intrinsic conduction as well as during right ventricular (RV) stimulation.

Results

In patients with narrow QRS and RBBB, the Q-LV/QRS ratio was 0.43?±?0.013 (n?=?20) and 0.41?±?0.026 (n?=?14), respectively. In patients with LBBB morphology, the Q-LV/QRS split up into a group of patients with normal (0.43?±?0.022, n?=?7) and a group with delayed left ventricular activation (0.75?±?0.016, n?=?18). By direct comparison of the Q-LV/QRS ratio during intrinsic conduction with the Q-LV/QRS ratio during RV pacing leading to a functional LBBB, a clear distinction between a group of “true LBBB” and another group of “apparent LBBB”/nonspecific intraventricular conduction delay (NICD) could be generated.

Conclusions

We present a novel and practical method that might facilitate discrimination between patients with apparent LBBB and true LBBB by comparing Q-LV/QRS ratios during intrinsic activation and during RV stimulation. Although this method can already be directly applied, validation by 3D electrical mapping and prospective correlation to cardiac resynchronization therapy (CRT) response will be required for further translation into clinical practice.

     

Plaque composition in the left main stem mimics the distal but not the proximal tract of the left coronary artery: influence of clinical presentation, length of the left main trunk, lipid profile, and systemic levels of C-reactive protein.

OBJECTIVES: We sought to investigate whether plaques located in the left main stem (LMS) differ in terms of necrotic core content from those sited in the proximal tract of the left coronary artery. BACKGROUND: Plaque composition, favoring propensity to vulnerability, might be nonuniformly distributed along the vessel, which might explain the greater likelihood for plaque erosion or rupture to occur in the proximal but not in the distal tracts of the coronary artery or in LMS. METHODS: A total of 72 patients were included prospectively; 48 (32 men; mean age 57 +/- 11 years; 25 with stable angina and 23 affected by acute coronary syndromes) underwent a satisfactory nonculprit vessel investigation through spectral analysis of intravascular ultrasound radiofrequency data (IVUS-Virtual Histology, Volcano Corp., Rancho Cordova, California). The region of interest was subsequently divided into LMS and LMS carina, followed by 6 consecutive nonoverlapping 6-mm segments in left anterior descending artery in 34 patients or in circumflex artery in 14 patients. RESULTS: Necrotic core content (%): 1) was minimal in LMS (median [interquartile range]: 4.6 [2 to 7]), peaked in the first 6-mm coronary segment (11.8 [8 to 16]; p < 0.01), and then progressively decreased distally; 2) was overall greater in patients with acute coronary syndromes (11.4 [5.5 to 19.8]) than stable angina (7.3 [3.2 to 12.9]; p < 0.001); 3) was largely independent from plaque size; and 4) did not correlate to systemic levels of C-reactive protein or lipid profile. CONCLUSIONS: Plaques located in the LMS carry minimal necrotic content. Thus, they mimic the distal but not the proximal tract of the left coronary artery, where plaque rupture or vessel occlusion occurs more frequently.     

Undetectable viral load is associated with sexual risk taking in HIV serodiscordant gay couples in Sydney

OBJECTIVE: To determine whether reporting that the HIV-positive partner's viral load is undetectable rather than detectable is associated with unprotected anal intercourse (UAI) in HIV serodiscordant gay couples. METHOD: A cross-sectional study nested within two cohort studies, the Health in Men (HIM) cohort of HIV-negative men, from July 2001 to December 2003 and the Positive Health (PH) cohort of HIV-positive men, from February 2002 to August 2003. The study participants were 119 men in an HIV serodiscordant regular relationship of at least 6 months duration (45 HIV-negative men from HIM, 74 HIV-positive men from PH). The main outcome measure was the occurrence of UAI within the relationship in the previous 6 months. RESULTS: Eighty-two men reported no UAI and 37 reported some UAI. Of couples in which the HIV-positive partner's viral load was reported to be undetectable, 39.4% reported UAI compared with 20.8% of those where viral load was reported to be detectable (P = 0.04). In multivariate analysis, significant predictors of UAI were younger age [odds ratio (OR), 0.94; 95% confidence interval (CI), 0.87-1.00; P = 0.05], greater HIV optimism (OR, 4.98; 95% CI, 1.25-19.8; P = 0.02) and reported undetectable viral load (OR, 2.88; 95% CI, 1.13-7.37; P = 0.03). CONCLUSIONS: Most serodiscordant gay couples do not engage in any UAI. UAI within such relationships is significantly more likely to occur where the HIV-positive partner is reported to have undetectable viral load. UAI in HIV serodiscordant relationships is problematic even if viral load is undetectable because of unknown risk parameters, viral load variability and the possibility of drug-resistant strains of HIV.     

Fluvastatin reduces the 4-year cardiac risk in patients with multivessel disease

BACKGROUND: To evaluate the impact of the extent of coronary disease (single- or multivessel) and of fluvastatin treatment on the incidence of long-term cardiac atherosclerotic complications in the Lescol Intervention Prevention Study (LIPS). METHODS: A total of 1063 patients with single-vessel disease and 614 patients with multivessel disease were randomized to receive fluvastatin (40 mg bid) or placebo for at least 3 years following a first successful percutaneous coronary intervention. The incidence of cardiac atherosclerotic events (cardiac death, non-fatal myocardial infarction, and coronary re-interventions not related to restenosis) was evaluated. RESULTS: Patients with multivessel disease tended to be older and presented a higher prevalence of associated risk factors and cardiovascular antecedents. The presence of multivessel disease markedly increased the risk of cardiac atherosclerotic events compared with single-vessel disease among patients allocated to placebo (RR 1.67 [95% CI: 1.24-2.25]; p<0.001). In patients treated with fluvastatin, however, no significant differences in long-term outcomes were observed between patients with multivessel disease and patients single-vessel disease (RR 1.28 [95% CI: 0.90-1.81]; p=0.2). CONCLUSIONS: Multivessel coronary disease impaired the 4-year outcomes after percutaneous intervention. However, the hazardous effect of multivessel disease was significantly reduced by long-term fluvastatin treatment.