Aix, SBPao and PWVao, measured oscillometrically, showed strong correlation with the invasively obtained values. The observed limits of agreement are encouragingly low for accepting the method for clinical use. Our results suggest that the PWVao values, measured by Arteriograph, are close to the true aortic PWV, determined invasively.

The Arteriograph is a new, easy-to-use and time-effective method for assessing arterial stiffness and wave reflection.

Objective. The measurement of aortic pulse wave velocity (PWV ao

1 Recent studies demonstrated that inhibition or genetic inactivation of the enzyme poly (ADPribose) polymerase (PARP) is bene®cial in myocardial reperfusion injury. PARP activation in the reperfused myocardium has been assumed, but not directly demonstrated. Furthermore, the issue whether pharmacological PARP inhibition a ords long-term functional bene®t in the reperfused myocardium has not been explored. These questions were addressed in the present study.2 In a rat model of myocardial ischemia (1 h) and reperfusion (up to 24 h), there was a marked and signi®cant activation of PARP in the ischemic borderzone, as determined by poly(ADP-ribose) (PAR) immunohistochemistry. PAR localized to the nuclei of myocytes and in®ltrating mononuclear cells. In the core of the infarction, necrotic tissues and di use PAR staining were observed. PARP activation remained markedly detectable 24 h after reperfusion. The PARP inhibitor 3-aminobenzamide (20 mg kg 71 intraperitoneally 10 min before reperfusion, and every 2 h thereafter for 6 h) markedly reduced the activation of the enzyme in myocytes. 3 3-aminobenzamide signi®cantly protected against myocardial morphological and functional alterations at 24 h post-reperfusion. Notably, infarct size was reduced, circulating creatine kinase activity was attenuated, and myocardial contractility (dP dt 71 ) was restored by 3-aminobenzamide. 4 Our results demonstrate a signi®cant and prolonged activation of PARP in the reperfused myocardium, localizing to the necrotic area and the ischaemic borderzone. Furthermore, the studies demonstrate that PARP inhibition a ords long-term bene®cial morphological and functional e ects in the reperfused myocardium. These data strengthen the notion that pharmacological PARP inhibition is a viable novel experimental approach for protection against myocardial reperfusion injury.

Abstract. Overactivation of the nuclear enzyme poly(ADPribose) polymerase (PARP) contributes to the development of cell dysfunction and tissue injury in various pathophysiological conditions associated with oxidative and nitrosative stress, including myocardial reperfusion injury, heart transplantation, diabetic cardiomyopathy and chronic heart failure. In recent studies, we have demonstrated the beneficial effects of a novel ultrapotent PARP inhibitor, INO-1001, on cardiac and endothelial dysfunction and remodeling in rat model of advanced aging-associated chronic heart failure and in a mouse model of heart failure induced by aortic banding. In the current study, we have investigated the effect of INO-1001 on the development of heart failure induced by permanent ligation of the left anterior descending coronary artery, heart failure induced by doxorubicin and acute myocardial dysfunction induced by bacterial endotoxin. In the coronary ligation model, a significantly depressed left ventricular performance and impaired vascular relaxation of aortic rings were found, and PARP inhibition significantly improved both cardiac function and vascular relaxation. In the doxorubicin model, a single injection of doxorubicin induced high mortality and a significant decrease in left ventricular systolic pressure, +dP/dt, -dP/dt, stroke volume, stroke work, ejection fraction and cardiac output. Treatment with the PARP inhibitor reduced doxorubicin-induced mortality and markedly improved cardiac function. PARP inhibition did not interfere with doxorubicin's antitumor effect. In the endotoxin model of cardiac dysfunction, PARP inhibition attenuated the suppression of myocardial contractility elicited by endotoxin. The current data strengthen the view that PARP inhibition may represent an effective approach for the experimental therapy of various forms of acute and chronic heart failure. IntroductionReactive oxygen and nitrogen species are overproduced in the cardiovascular system during chronic heart failure. Oxidantinduced cell injury involves the activation of a nuclear enzyme, poly(ADP-ribose) polymerase (PARP), which importantly contributes to the development of cell dysfunction and tissue injury in various pathophysiological conditions associated with oxidative and nitrosative stress, including myocardial reperfusion injury, heart transplantation, diabetic cardiomyopathy and chronic heart failure (overviewed in refs. 1,2).Recent studies have demonstrated the cardioprotective effect of a novel ultrapotent poly(ADP-ribose) polymerase (PARP) inhibitor, INO-1001 on the development of cardiac hypertrophy and cardiac contractile dysfunction in rat model of advanced aging-associated chronic heart failure and in a murine model of chronic heart failure induced by aortic banding (3,4). In the present study, we investigated the effect of INO-1001 on the cardiac function in three additional models of cardiac dysfunction: a) chronic heart failure induced by chronic ligation of the left anterior descending coronary artery; b) heart failu...

The enhanced wave reflection in small children is a well-known phenomenon. It is explained on the basis of differences in the body height and the timing of wave reflection. This hypothesis still has not been proved directly. The aim of our study was to determine the reference values of aortic augmentation index (Aix(ao)) and the simultaneously measured return time of the systolic pulse wave (RT) in relation to the body height to test this hypothesis. Aix(ao) and RT were measured by Arteriograph in a healthy population aged 3-18 years (n = 4619, 2489 males). The Aix(ao) decreased with increasing age in boys from 18.6 ± 8.4% to 4.7 ± 4.3% and in girls from 22.3 ± 9.2% to 8.1 ± 5.1%, whereas the RT increased from 115.5 ± 16.3 ms to 166.7 ± 20.8 ms in boys and from 106.7 ± 21.9 ms to 158.1 ± 15.5 ms in girls. These changes were constant during childhood, but they slowed down after the onset of puberty. Because aortic pulse wave velocity (PWV(ao)) measured in the same population was unchanged during childhood, the increase of RT can only be explained by the increase of aortic length due to growth. In the puberty PWV(ao) starts increasing indicating that RT (Aix(ao)) does not follow the increase (decrease) of aortic length proportionally.

Poly(ADP-ribose) polymerase (PARP) activation plays a key role in free radical-induced injury in the context of systemic inflammation and ischemia/reperfusion. In the present preclinical study, we investigated the effects of INO-1001, a novel PARP inhibitor, on cardiac and pulmonary function during reperfusion in an experimental model of cardioplegic arrest and extracorporal circulation. Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 min of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6), or INO-1001 (1 mg/kg), a potent PARP inhibitor (n = 6). Biventricular hemodynamic variables were measured by combined pressure-volume-conductance catheters. Coronary and pulmonary blood flow and vasodilative responses to acetylcholine and sodium nitroprusside as well as pulmonary gas exchange were also determined. The administration of INO-1001 led to a significantly better recovery of left and right ventricular systolic function (P < 0.05) after 60 min of reperfusion. Coronary blood flow was also significantly higher in the INO-1001 group (P < 0.05). Although the vasodilative response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly greater increase in coronary and pulmonary blood flow in the INO-1001 group (P < 0.05). Pulmonary function in terms of alveolar arterial oxygen difference was better preserved in the INO-1001-treated group (P < 0.05). Thus, PARP inhibition improves the recovery of myocardial and endothelial function after hypothermic cardiac arrest and reduces pulmonary injury associated with extracorporal circulation.

Background: Arterial stiffness parameters are commonly used to determine the development of atherosclerotic disease. The independent predictive value of aortic stiffness has been demonstrated for coronary events. Hypothesis: The aim of our study was to compare regional and local arterial functional parameters measured by 2 different noninvasive methods in patients with verified coronary artery disease (CAD). We also compared and contrasted these stiffness parameters to the coronary SYNTAX score in patients who had undergone coronary angiography. Methods: In this study, 125 CAD patients were involved, and similar noninvasive measurements were performed on 125 healthy subjects. The regional velocity of the aortic pulse wave (PWVao) was measured by a novel oscillometric device, and the common carotid artery was studied by a Doppler echo-tracking system to determine the local carotid pulse wave velocity (PWVcar). The augmentation index (AIx), which varies proportionately with the resistance of the small arteries, was recorded simultaneously. Results: In the CAD group, the PWVao and aortic augmentation index (Alxao) values increased significantly (10.1 ± 2.3 m/sec and 34.2% ± 14.6%) compared to the control group (9.6 ± 1.5 m/sec and 30.9% ± 12%; P < 0.05). We observed similar significant increases in the local stiffness parameters (PWVcar and carotid augmentation index [Alxcar]) in patients with verified CAD. Further, we found a strong correlation for PWV and AIx values that were measured with the Arteriograph and those obtained using the echo-tracking method (r = 0.57, P < 0.001 for PWV; and r = 0.65, P < 0.001 for AIx values). Conclusions: Our results indicate that local and regional arterial stiffness parameters provide similar information on impaired arterial stiffening in patients with verified CAD.