Omar Ali

Circulating Endothelial Progenitor Cells in Patients With Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension

Background— Impaired endothelial homeostasis underlies the pathophysiology of pulmonary arterial hypertension (PAH). We speculated that PAH patients are deficient in circulating endothelial progenitor cells (EPCs), potentially contributing to endothelial dysfunction and disease progression. Methods and Results— We recruited 41 patients with Eisenmenger syndrome (13 with Down syndrome), 55 with idiopathic PAH, and 47 healthy control subjects. Flow cytometry and in vitro assays were used to quantify EPCs and to assess cell function. The number of circulating CD34+, CD34+/AC133+, CD34+/KDR+, and CD34+/AC133+/KDR+ progenitor cells was low in Eisenmenger patients compared with healthy control subjects, and those with Down syndrome displayed even fewer EPCs. Reductions in EPC numbers correlated with New York Heart Association functional class, 6-minute walk distance, and plasma brain-type natriuretic peptide levels. The capacity of cultured peripheral blood mononuclear cells to form colonies and incorporate into tube-like structures was impaired in Eisenmenger patients. Idiopathic PAH patients had reduced numbers of EPCs, and the number of circulating EPCs correlated with invasive hemodynamic parameters in this cohort. Levels of immune inflammatory markers, cGMP, stable nitric oxide oxidation products, and asymmetric dimethylarginine were abnormal in patients with PAH and related to numbers of EPCs. Within the idiopathic PAH population, treatment with the phosphodiesterase inhibitor sildenafil was associated with a dose-dependent rise in EPC numbers, resulting in levels consistently above those found with other therapies. Conclusions— Circulating EPC numbers are reduced in 2 well-characterized forms of PAH, which also exhibit raised levels of inflammatory mediators. Sildenafil treatment may represent a pharmacological means of increasing circulating EPC numbers long-term.

Simvastatin as a Treatment for Pulmonary Hypertension Trial

RATIONALE In animal models of pulmonary hypertension, simvastatin has been shown to reduce pulmonary artery pressure and induce regression of associated right ventricular (RV) hypertrophy. OBJECTIVES To assess the therapeutic value of simvastatin in patients with pulmonary arterial hypertension (PAH). METHODS Forty-two patients with PAH were randomized to receive either simvastatin (80 mg/d) or placebo in addition to current care for 6 months, and thereafter offered open-label simvastatin. The primary outcome was change in RV mass, assessed by cardiac magnetic resonance (CMR). MEASUREMENTS AND MAIN RESULTS At 6 months, RV mass decreased by 5.2 +/- 11 g in the statin group (P = 0.045) and increased 3.9 +/- 14 g in the placebo group. The treatment effect was -9.1 g (P = 0.028). N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels decreased significantly in the statin group (-75 +/- 167 fmol/ml; P = 0.02) but not the placebo group (49 +/- 224 fmol/ml; P = 0.43; overall treatment effect -124 fmol/ml; P = 0.041). There were no significant changes in other outcome measures (including 6-minute walk test, cardiac index, and circulating cytokines). From 6 to 12 months, both RV mass and NT-proBNP increased toward baseline values in 16 patients on active treatment who continued with simvastatin but remained stable in 18 patients who switched from placebo to simvastatin. Two patients required a reduction in dose but not cessation of simvastatin. CONCLUSIONS Simvastatin added to conventional therapy produces a small and transient early reduction in RV mass and NT-proBNP levels in patients with PAH, but this is not sustained over 12 months.

Improved cardiac survival, freedom from MACE and angina-related quality of life after successful percutaneous recanalization of coronary artery chronic total occlusions.

BACKGROUND Most percutaneous recanalizations of coronary artery chronic total occlusion (CTO) are not attempted because of the skepticism on their long-term clinical benefit. We assessed the effect of percutaneous CTO recanalization procedures on long-term cardiac survival, freedom from MACE and angina-related quality of life (AQL). METHODS All consecutive patients who underwent attempt of percutaneous native coronary artery CTO recanalization between 2003 and 2009 were included in the study. MACE was defined as combined cardiac death, myocardial infarction (MI) and target vessel revascularization (TVR). AQL was assessed by the Seattle Angina Questionnaire-UK-version (SAQ-UK). RESULTS Among 302 patients who received an attempt of percutaneous CTO recanalization, 237 (78%) had a successful procedure while in 65 (22%) the procedure failed. Overall intra-hospital complication rate was 3.0%, with no difference between the two groups. Median follow-up was 4.0 years, during which 13 patients had a fatal cardiac event. Patients in whom the CTO recanalization procedure failed had a higher risk of cardiac death (HR 3.39; 95% CI 1.14-10.1;p=0.03; after propensity score adjustment, HR 2.83; 95% CI 0.89-8.96;p=0.07) and MACE (HR 5.40; 95% CI 2.71-10.5;p<0.001; adjusted HR 3.34; 95% CI 1.47-7.58;p=0.003) compared to patients with successful procedure. CTO recanalization significantly improved the AQL during follow-up: patients with successful procedure experienced less physical activity limitation (p=0.01), rarer angina episodes (p<0.001) and greater treatment satisfaction (p=0.03) compared to patients with failed procedure. CONCLUSIONS Patients with successful CTO recanalization had a trend towards better cardiac survival and significant lower risk of MACE and improvement of AQL compared to patients with failed procedures.

Pleiotropic effects of statins in distal human pulmonary artery smooth muscle cells

BackgroundRecent clinical data suggest statins have transient but significant effects in patients with pulmonary arterial hypertension. In this study we explored the molecular effects of statins on distal human pulmonary artery smooth muscle cells (PASMCs) and their relevance to proliferation and apoptosis in pulmonary arterial hypertension.MethodsPrimary distal human PASMCs from patients and controls were treated with lipophilic (simvastatin, atorvastatin, mevastatin and fluvastatin), lipophobic (pravastatin) and nitric-oxide releasing statins and studied in terms of their DNA synthesis, proliferation, apoptosis, matrix metalloproteinase-9 and endothelin-1 release.ResultsTreatment of human PASMCs with selected statins inhibited DNA synthesis, proliferation and matrix metalloproteinase-9 production in a concentration-dependent manner. Statins differed in their effectiveness, the rank order of anti-mitogenic potency being simvastatin > atorvastatin > > pravastatin. Nevertheless, a novel nitric oxide-releasing derivative of pravastatin (NCX 6550) was effective. Lipophilic statins, such as simvastatin, also enhanced the anti-proliferative effects of iloprost and sildenafil, promoted apoptosis and inhibited the release of the mitogen and survival factor endothelin-1. These effects were reversed by mevalonate and the isoprenoid intermediate geranylgeranylpyrophosphate and were mimicked by inhibitors of the Rho and Rho-kinase.ConclusionsLipophilic statins exert direct effects on distal human PASMCs and are likely to involve inhibition of Rho GTPase signalling. These findings compliment some of the recently documented effects in patients with pulmonary arterial hypertension.

Emerging therapies for pulmonary arterial hypertension

Pulmonary arterial hypertension is characterised by increased pulmonary vascular resistance due to increased vascular tone and structural remodelling of pulmonary vessels. The therapies that are in use so far have been developed to correct endothelial dysfunction and reduce vasomotor tone. These treatments have a limited effect on the remodelling process and, increasingly, the focus is turning to potent strategies for inhibiting vascular proliferation and promoting vascular apoptosis. Multiple novel targets have been uncovered over the last 5 years and several are now in early clinical trials. At present, it is clear that there is no single treatment for the condition. Although this is the case, studies are investigating the role of combining therapies that are already established.

High incidence of acute coronary occlusion in patients without protocol positive ST segment elevation referred to an open access primary angioplasty programme.

Background Primary percutaneous coronary intervention (PPCI) programmes vary in admission criteria from open referral to acceptance of electrocardiogram (ECG) protocol positive patients only. Rigid criteria may result in some patients with acutely occluded coronary arteries not receiving timely reperfusion therapy. Objective To compare the prevalence of acute coronary occlusion and, in these cases, single time point biomarker estimates of myocardial infarct size between patients presenting with protocol positive ECG changes and those presenting with less diagnostic changes in the primary angioplasty cohort of an open access PPCI programme. Methods We retrospectively performed a single centre cross sectional analysis of consecutive patients receiving PPCI between January and August 2008. Cases were categorised according to presenting ECG—group A: protocol positive (ST segment elevation/left bundle branch block/posterior ST elevation myocardial infarction), group B: ST segment depression or T-wave inversion, or group C: minor ECG changes. Clinical characteristics, coronary flow grades and 12 h postprocedure troponin-I levels were reviewed. Results During the study period there were 513 activations of the PPCI service, of which 390 underwent immediate angiography and 308 underwent PPCI. Of those undergoing PPCI, 221 (72%) were in group A, 41 (13%) in group B and 46 (15%) in group C. Prevalence of coronary occlusion was 75% in group A compared with 73% in group B and 63% in group C. Median 12 h postintervention troponin-I (25th–75th percentile) for those with coronary occlusion was significantly higher in group A patients; 28.9 μg/l (13.2–58.5) versus 18.1 μg/l (6.7–32.4) for group B (p=0.03); and 15.5 μg/l (3.8–22.0) for group C (p<0.001), suggesting greater infarct size in group A. Conclusions A number of patients referred to an open access PPCI programme have protocol negative ECGs but myocardial infarction and acute coronary artery occlusion amenable to angioplasty.

Response to Letter Regarding Article, “Circulating Endothelial Progenitor Cells in Patients With Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension”

We thank Dr Asosingh et al for their interest in our study.1 Apparent disparity with their data2 probably reflects, at least in part, differences in defining endothelial progenitor cells (EPCs) and the number of patients studied with idiopathic pulmonary arterial hypertension. Asosingh et al2 measured only CD34+ …

A feasibility and safety study of intracoronary hemodilution during primary coronary angioplasty in order to reduce reperfusion injury in myocardial infarction.

We designed a pilot study to evaluate safety and feasibility of an inexpensive and simple approach to intracoronary hemodilution during primary angioplasty (PPCI) to reduce reperfusion injury.