Chronic overcirculation-induced pulmonary arterial hypertension in aorto-caval shunt.

Pulmonary arterial hypertension is a common complication of congenital heart defects with left-to-right shunts. Current preclinical models do not reproduce clinical characteristics of shunt-related pulmonary hypertension. Aorto-caval shunt was firstly described as a model of right ventricle volume overload. The pathophysiology and the possible determination of pulmonary arterial hypertension of different periods of shunt exposure are still undefined. A method to create standardized, reproducible aorto-caval shunt was developed in growing rats (260±40 g). Three groups of animals were considered: shunt exposure for 10 weeks, shunt exposure for 20 weeks and control (sham laparotomy). Echocardiography and magnetic resonance revealed increased right ventricular end diastolic area in shunt at 10 weeks compared to control. Hemodynamic analysis demonstrated increased right ventricular afterload and increased effective pulmonary arterial elastance (Ea) in shunt at 20 weeks compared to control (1.29±0.20 vs. 0.14±0.06 mmHg/µl, p=0.004). At the same time point, the maximal slope of end-systolic pressure-volume relationship (Ees) decreased (0.5±0.2 mmHg/ml vs. 1.2±0.3, p<0.001). Consequently, right ventricular-arterial coupling was markedly deteriorated with a ≈50% decrease in the ratio of end-systolic to pulmonary artery elastance (Ees/Ea). Finally, left ventricular preload diminished (≈30% decrease in left ventricular end-diastolic volume). Histology demonstrated medial hypertrophy and small artery luminal narrowing. Chronic exposure to aorto-caval shunt is a reliable model to produce right ventricular volume overload and secondary pulmonary arterial hypertension. This model could be an alternative with low mortality and high reproducibility for investigators on the underlying mechanisms of shunt-related pulmonary hypertension.

"Polarizing" microplegia improves cardiac cycle efficiency after CABG for unstable angina.

BACKGROUND: Myocardial protection during coronary artery bypass grafting (CABG) for unstable angina (UA) still represents a major challenge, ought to the risk for further ischemia/reperfusion injury. Few studies investigate the biochemical, hemodynamic and echocardiographic results of microplegia (Mic) in UA. METHODS: Eighty UA-patients undergoing CABG were randomized to Mic (Mic-Group) or standard 4:1 blood Buckberg-cardioplegia (Buck-Group). Troponin-I and lactate were sampled from coronary sinus at reperfusion (T1), and from peripheral blood preoperatively (T0), at 6 (T2), 12 (T3) and 48 (T4) hours. Cardiac index (CI), indexed systemic vascular resistances (ISVR), Δp/Δt, cardiac cycle efficiency (CCE), and central venous pressure (CVP) were collected preoperatively (T0), and since Intensive Care Unit (ICU)-arrival (T1) to 24h (T5). Echocardiographic E-wave (E), A-wave (A), E/A, peak early-diastolic TDI-mitral annular-velocity (Ea), and E/Ea investigated the diastolic function and Wall Motion Score Index (WMSI) the systolic function, preoperatively (T0) and at 96h (T1). RESULTS: Mic-Group showed lower troponin-I and lactate from coronary sinus (p=.0001 for both) and during the postoperative course (between-groups p=.001 and .0001, respectively). WMSI improved only after Mic (time-p=.001). Higher CI Δp/Δt and CCE (between-groups p=.0001), with comparable CVP and ISVR (p=N.S.) were detected after Mic. Diastolic function improved in both groups, but better after Mic (between-groups p=.003, .001, and .013 for E, E/A, and Ea, respectively). Mic resulted in lower transfusions (p=.006) and hospitalization (p=.002), and a trend towards lower need/duration of inotropes (p=.04 and p=.041, respectively), and ICU-stay (p=.015). CONCLUSION: Microplegia attenuates myocardial damage in UA, reduces transfusions, improves postoperative systo-diastolic function, and shortens hospitalization.

Benefits from small molecule administration as compared with abciximab among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a meta-analysis.

OBJECTIVES: The aim of the study was to perform a meta-analysis of randomized trials (RTs) comparing abciximab versus small molecules (eptifibatide and tirofiban) in primary angioplasty (PPCI) for ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Abciximab has been shown to provide significant benefits in PPCI for STEMI. However, small molecules represent an attractive strategy due to the reversibility of the inhibition of platelet aggregation and the lower costs. METHODS: We obtained results from RTs comparing abciximab versus small molecules in PPCI. The literature was scanned by searches of electronic databases (MEDLINE and CENTRAL) up to October 2008. The following key words were used: RT, myocardial infarction, reperfusion, primary angioplasty, glycoprotein IIb/IIIa inhibitors, abciximab, tirofiban, and eptifibatide. Concerning tirofiban, we only included trials or groups of patients with high-dose bolus and infusion. The primary end point was 30-day mortality. Secondary end points were 30-day reinfarction, post-procedural Thrombolysis In Myocardial Infarction (TIMI) flow grade 3, and ST-segment resolution. RESULTS: A total of 6 RTs were included in the meta-analysis, involving 2,197 patients (1,082 randomized to abciximab and 1,115 to small molecules [high-dose tirofiban in 5 trials and eptifibatide in 1 trial]). Abciximab did not improve post-procedural TIMI flow grade 3 (89.8% vs. 89.1%, p = 0.72) or ST-segment resolution (67.8% vs. 68.2%, p = 0.66). Abciximab did not reduce 30-day mortality (2.2% vs. 2.0%, p = 0.66) or reinfarction (1.2% vs. 1.2%, p = 0.88), nor was there any difference in major bleeding complications (1.3% vs. 1.9%, p = 0.27). CONCLUSIONS: This meta-analysis shows among STEMI patients undergoing PPCI similar results between abciximab and small molecules in terms of angiographic, electrocardiographic, and clinical outcome.

The role of neopterin in cardiovascular disease.

Inflammation plays a key role in the initiation and progression of atherosclerosis but also in the pathophysiology of atheromatous plaque disruption and the development of acute coronary syndromes. Neopterin is a marker of inflammation and of immune system activation, it is synthesized by macrophages, that, once activated, release this substance. Indeed, in clinical evaluation of patients, measurements of plasma levels of neopterin are usually used to evaluate progression of viral infections, renal transplant rejection, severe systemic inflammatory diseases, nephritic syndrome and several autoimmune diseases. This mediator is able to induce a pro-atherothrombotic phenotype in cells of the coronary circulation. Recent data indicate that serum levels of neopterin are elevated in patients with coronary and peripheral artery disease and seem to be a prognostic marker for major adverse cardiovascular events. In particular, neopterin levels predict future major cardiac and vascular adverse events in patients presenting with chronic coronary artery disease, with acute coronary syndromes, and in those with critical limb ischemia. This renders this molecule a useful marker of atherosclerotic plaque activity, permitting the identification of the subjects at highest risk for major adverse cardiovascular events. In line with the above mentioned evidences, patients with high neopterin levels may require aggressive risk factor modification and intensive medical treatment irrespective of the severity of their coronary artery disease. This data suggest a potential clinical use of neopterin as a marker for disease activity in patients with cardiovascular disease.

HMG-CoA reductase inhibitors reduce nicotine-induced expression of cellular adhesion molecules in cultured human coronary endothelial cells.

BACKGROUND: Smoking predisposes to the development of atherosclerosis and of its complications. The mechanisms responsible for these effects are not completely understood. We have investigated whether nicotine might promote a proatherosclerotic state in human coronary endothelial cells (HCAECs), studying the role of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in preventing these phenomena. METHODS AND RESULTS: Real-time PCR showed that nicotine induced a dose-dependent increase in mRNA levels for vascular cellular adhesion molecule-1 (VCAM-1)/intercellular adhesion molecule-1 (ICAM-1). Fluorescent-activated cell sorting analysis showed that nicotine induced expression of functionally active VCAM-1/ICAM-1, since they increased leukocyte adherence to HCAECs. Oxygen free radicals, Rho A and nuclear factor kappaB (NF-kappaB) play a pivotal role in modulating these effects. Indeed, nicotine caused oxygen free radical production as well as activation of Rho A and NF-kappaB pathways, evaluated by malondialdehyde levels, pulldown assay and by electrophoretic mobility shift assay, respectively. Superoxide dimutase, Rho A (Y-27639) and NF-kappaB inhibitors (pyrrolidine dithiocarbamate ammonium, Bay 11-7082) suppressed nicotine effects on CAM expression. HMG-CoA reductase inhibitors prevented these nicotine-mediated effects by inhibiting free radical generation and by modulating activation of Rho A and NF-kappaB pathways. CONCLUSIONS: Nicotine promotes CAM expression on HCAECs, shifting them toward a proatherosclerotic state. These effects might explain, at least in part, the deleterious cardiovascular consequences of cigarette smoking. HMG-CoA reductase inhibitors play an important role in preventing these phenomena.