Journal of Cardiovascular Pharmacology and Therapeutics

We explored the impact of rosiglitazone on endothelial function in normal volunteers and its interaction with glyceryl trinitrate (GTN)-induced abnormalities in endothelial function. We hypothesized that rosiglitazone would have a neutral effect on endothelial function in normal volunteers and would favorably modify endothelial dysfunction induced by GTN.

In this double-blind, randomized, placebo-controlled study, 44 participants were randomized to placebo, rosiglitazone (4 mg twice daily), transdermal GTN (0.6 mg/h), or both GTN and rosiglitazone. After 7 days of treatment, participants underwent measures of forearm blood flow during brachial artery infusion of acetylcholine (Ach). Serum glucose concentrations and insulin sensitivity were assessed.

Unexpectedly, rosiglitazone-treated participants experienced blunted responses to endothelium-dependent responses to Ach (P < .05 vs placebo). Sustained GTN administration caused similar abnormalities in endothelial function (P < .05 vs placebo) and rosiglitazone + GTN (P < .05 vs placebo; P = ns vs rosiglitazone). Interestingly, co-infusion of the antioxidant vitamin C improved endothelial responses in those randomized to rosiglitazone and GTN alone (P = not significant [ns] compared with placebo), but it did not improve endothelial function in those treated with rosiglitazone + GTN. Neither rosiglitazone nor GTN treatment modified the measures of glucose metabolism.

Unexpectedly, therapy with rosiglitazone caused abnormalities in endothelial function in normal volunteers. These findings have important implications with respect to drug development and surveillance.

Low cholesterol levels are associated with a worse outcome in patients with heart failure (HF). Use of statins in HF remains controversial. We aimed to assess whether the prognosis of patients with intrinsically low cholesterol levels differed from that of those with pharmacologically induced low cholesterol.

We conducted a retrospective cohort study on 464 ambulatory patients attending a specialized HF clinic. Patients were cross-classified according to statin therapy and admission total cholesterol level (low cholesterol <150 mg/dL and cholesterol ≥150 mg/dL): (1) low total cholesterol level on statin therapy; (2) low total cholesterol level not taking statins; (3) cholesterol ≥150 mg/dL on statin therapy; and (4) cholesterol ≥150 mg/dL not on statin therapy. Patients were followed up to 5 years and the outcome was all-cause death. A Cox regression analysis was used in prognosis assessment.

Almost two thirds of the patients were men and the median population age was 69 years; 22.8% of the patients had preserved ejection fraction and 43.5% severe systolic dysfunction. The patients with an intrinsically low cholesterol had a hazard ratio of all-cause death up to 5 years of 2.38 (1.08-7.14) compared to those with low cholesterol induced by statin use. This association was independent of other variables associated with outcome.

Patients with HF with instrisically low cholesterol levels have a double risk of death up to 5 years compared to patients with pharmacologically induced low cholesterol. Clinicians should not limit the use of statins by fear of lowering the cholesterol levels.

African Americans have greater risk of cardiovascular events than comparator populations of white European origin. A potential reason for this is reduced nitric oxide bioavailability in African Americans, resulting in increased prevalence of factors that contribute to ventricular dysfunction. We investigated the effects of nebivolol with the diuretic hydrochlorothiazide (HCTZ) in hypertensive African Americans with echocardiographic evidence of diastolic dysfunction.

A total of 42 African American patients were assigned to nebivolol and HCTZ in an open-label fashion for a 24-week period. Changes in blood pressure (BP), echocardiographic parameters, and success in attaining target BP were determined. As an indirect determinant of endothelial function, serum total nitric oxide (NOx) levels and asymmetric dimethyl arginine (ADMA) levels were performed at baseline and after the treatment period.

The systolic BP decreased from 150 ± 13 to 136 ± 16 mm Hg (P < .005). Diastolic BP decreased from 94 ± 13 to 84 ± 9 mm Hg (P = .008). Of the patients that completed the study, 77% achieved a combined target BP of systolic BP <140 mm Hg and a diastolic BP <90 mm Hg. Serum NOx increased by 41% and 39% in patients that were treated with 10 mg and 20 mg daily nebivolol, respectively. The ADMA levels decreased by 44% following treatment. The change in systolic BP was strongly correlated to the change in ADMA (r = .54; P = .024). Furthermore, in comparison to a group of age-matched patients controlled with diuretic therapy only, the ADMA levels were significantly lower in the nebivolol posttreatment group (controlled BP with diuretic: 0.32 ± 0.07μmol/L; nebivolol posttreatment: 0.24 ± 0.06 μmol/L; P < .05).

Reduced BP with nebivolol in hypertensive African Americans and echocardiographic evidence of diastolic dysfunction correlates with improved endothelial function. Furthermore, improvement in endothelial function and increased nitric oxide bioavailability suggests a potential mechanism of efficacy of nebivolol in these patients.

Bacteremia during elective tonsillectomy is well recognized, whereas bacteremia during quinsy tonsillectomy has never been studied. The aim of the present study was to explore the incidence of bacteremia during elective and quinsy tonsillectomy in order to evaluate the antibiotic prophylaxis recommendations to patients at high risk of infective endocarditis who are undergoing tonsillectomy.

A prospective study was conducted on 80 patients undergoing elective tonsillectomy and 36 patients undergoing acute tonsillectomy due to peritonsillar abscess. Blood cultures, tonsillar swabs, core tissue, and pus aspirates were analyzed by standard microbiological techniques.

Bacteremia was detected in 73% of patients during elective tonsillectomy compared to 56% during quinsy tonsillectomy (P = .089, Fishers exact test). Significantly more blood culture bottles were positive for each isolate obtained from elective tonsillectomy cases compared to quinsy tonsillectomy cases (P < .001, Spearman rank correlation). In all, 59% and 42% of electively and acutely tonsillectomized patients, respectively, had bacteremia with microorganisms that are predominant in bacterial endocarditis. Ninety-three percent of the isolated strains were sensitive to amoxicillin, and all were sensitive to amoxicillin with clavulanic acid.

Our results challenge the distinction made by the European Society of Cardiology between elective and quinsy tonsillectomy, with regard to antibiotic prophylaxis recommendation only to patients undergoing procedures to treat an established infection. To provide full empiric coverage, including coverage for Staphylococcus aureus, we advocate the use of amoxicillin with clavulanic acid in patients at high risk of infective endocarditis.

To evaluate the therapeutic effects of prostaglandin E₁ (PGE₁) on residual pulmonary arterial hypertension (PAH) after corrective surgery for congenital heart disease.

Thirty-one patients with postoperational PAH were randomly divided into control group (n = 15) and PGE₁ group (n = 16, 6 courses of intravenous PGE₁ plus conventional therapy). Mean pulmonary arterial pressure (MPAP), right ventricular ejection fraction (RVEF), and left ventricular ejection fraction (LVEF) were measured by echocardiography before and 3, 6, and 12 months after the treatment. Arterial oxygen pressure (Pao ₂) was monitored.

In both groups, MPAP decreased and RVEF, LVEF, and Pao ₂ increased at 6 and 12 months following surgery. In the PGE₁ group, the MPAP (32.2 ± 5.2 vs 40.2 ± 5.1 mm Hg; P = .008) was lower and RVEF (66.6% ± 6.5% vs 54.9% ± 2.1%; P = .019), LVEF (65.9% ± 3.9% vs 53.5% ± 5.1%; P = .031), and Pao ₂ (94.3% ± 11.2% vs 93.1% ± 11.3%; P = .009) was higher than in the control group 12 months after the surgery. Four patients (26.7%) in the control group died of pulmonary hypertension crisis, but there was no death in the PGE₁ group (P = .029). Cumulative survival rate in the control group were 86.7%, 80%, 73.3%, and 73.3% at 1, 2, 3, and 5 years, respectively.

Intravenous PGE₁ therapy after corrective surgery for congenital heart disease was associated with a reduction in mean pulmonary arterial pressure and a lower risk of death.

The purpose of this study is to investigate the potential in vivo antiplatelet and thromboprotective properties of the antihypertensive drug losartan in mice.

Aggregometry studies were performed on platelets obtained from mice administered losartan for 5 days, via tail vein to examine the ex vivo effects (dose dependence) of this agent and to select an appropriate dose for the in vivo studies. Next, the tail bleeding time test and the time for occlusion in a carotid artery injury thrombosis model (ferric chloride) were also performed to assess the in vivo effects of losartan treatment.

These data indicate that the antihypertensive agent losartan exerts dose-dependent inhibition of the thromboxane receptor-mediated (U46619/agonist)-induced platelet aggregation (ex vivo), whereas it produced no detectable effects on aggregation triggered by adenosine diphosphate or the thrombin receptor activating peptide 4. Findings from the in vivo analysis revealed that tail bleeding time of losartan-treated mice was not different from vehicle-treated mice. On the other hand, in the carotid artery injury thrombosis model, it was found that the losartan-treated mice had significantly longer time for occlusion in comparison with those treated with vehicle control.

These findings provide evidence that administration of the antihypertensive drug losartan into live mice produces thromboxane A₂ receptor–specific antiplatelet effects. Furthermore, interestingly, this antiplatelet activity appears to translate into thromboprotective properties, without resulting in a bleeding phenotype. Consequently, aside from its potential use as an antithrombotic agent, losartan’s chemistry may provide a “blueprint” for designing or repurposing novel derivatives which may have the potential to serve as an antiplatelet and thromboprotective agents but are deprived of the usually concomitant bleeding adverse effects.

Synthetic class A amphipathic helical peptide analogs of apolipoprotein-AI (apoAI; with varied phenylalanine residues) are emerging therapeutic approaches under investigation for atherosclerosis. Utilizing retroinverso sequencing, we designed reverse-D4F (Rev-D4F) peptide with 18 d-amino acids containing 4 phenylalanine residues and reverse order that allows the side chain residues to be of exact alignment and superimposable to those of the parent l-amino acid peptide. This study examined the effect of Rev-D4F on atherosclerosis in apolipoprotein E (apoE)-null mice and the underlying mechanisms.

ApoE-null mice were fed a chow diet and administered water (control), Rev-D4F, or L4F mimetic peptides (0.4 mg/mL, equivalent to 1.6 mg/d) orally in drinking water for 6 weeks. Aortic root atherosclerotic lesion area, lesion macrophage content, and the ability of plasma high-density lipoprotein (HDL) to influence monocyte chemotaxis were measured.

Rev-D4F significantly decreased aortic sinus atherosclerotic lesion area and lesion macrophage content without affecting plasma total and HDL-cholesterol levels in apoE-null mice. The HDL from Rev-D4F-treated mice showed enhanced anti-inflammatory monocyte chemotactic activity, while low-density lipoprotein (LDL) exhibited reduced proinflammatory activity. In in vitro studies, Rev-D4F inhibited LDL oxidation, endothelial cell vascular cell adhesion molecule 1 (VCAM-1), and monocyte chemotactic factor 1 (MCP-1) expression, and monocyte adhesion to aortic endothelial cells.

The Rev-D4F inhibits atherosclerosis by inhibiting endothelial inflammatory/oxidative events and improving HDL function. The data suggest that Rev-D4F may be an effective apoAI mimetic peptide for further development in preventing atherosclerosis.