Omar Nass

Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors.

Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolong survival in patients with heart failure (HF). Blockade of the renin-angiotensin system (RAS) with an angiotensin II type 1 receptor antagonist (AT1-ant) may have a similar beneficial effect. In addition to inhibition of the RAS, ACEi may also act by inhibiting kinin destruction, whereas AT1-ant may block the RAS at the level of the AT1 receptor and activate the angiotensin II type 2 (AT2) receptor. Using a model of HF induced by myocardial infarction (MI) in rats, we studied the role of kinins in the cardioprotective effect of ACEi. We also investigated whether an AT1-ant has a similar effect and whether these effects are partly due to activation of the AT2 receptor. Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B2 receptor antagonist icatibant (B2-ant); or (c) an AT1-ant with and without an AT2-antagonist (AT2-ant) or B2-ant. Vehicle-treated rats had a significant increase in left ventricular end-diastolic (LVEDV) and end-systolic volume (LVESV) as well as interstitial collagen deposition and cardiomyocyte size, whereas ejection fraction was decreased. Left ventricular remodeling and cardiac function were improved by the ACEi and AT1-ant. The B2-ant blocked most of the cardioprotective effect of the ACEi, whereas the effect of the AT1-ant was blocked by the AT2-ant. The decreases in LVEDV and LVESV caused by the AT1-ant were also partially blocked by the B2-ant. We concluded that (a) in HF both ACEi and AT1-ant have a cardioprotective effect, which could be due to either a direct action on the heart or secondary to altered hemodynamics, or both; and (b) the effect of the ACEi is mediated in part by kinins, whereas that of the AT1-ant is triggered by activation of the AT2 receptor and is also mediated in part by kinins. We speculate that in HF, blockade of AT1 receptors increases both renin and angiotensins; these angiotensins stimulate the AT2 receptor, which in turn may play an important role in the therapeutic effect of the AT1-ant via kinins and other autacoids.

Cardiac contractility modulation with the impulse dynamics signal: studies in dogs with chronic heart failure.

The intravenous use of positive inotropic agents, such as sympathomimetics and phosphodiesterase inhibitors, in heart failure is limited by pro-arrhythmic and positive chronotropic effects. Chronic use of these agents, while eliciting an improvement in the quality of life of patients with advanced heart failure, has been abandoned because of marked increase in mortality when compared to placebo. Nevertheless, patients with advanced heart failure can benefit from long-term positive inotropic support if the therapy can be delivered ‘on demand’ and in a manner that is both safe and effective. In this review, we will examine the use of a novel, non-stimulatory electrical signal that can acutely modulate left ventricular (LV) contractility in dogs with chronic heart failure in such a way as to elicit a positive inotropic support. Cardiac contractility modulation (CCM) with the Impulse Dynamic™ signal was examined in dogs with chronic heart failure produced by intracoronary microembolizations. Delivery of the CCM signal from a lead placed in the great coronary vein for periods up to 10 minutes resulted in significant improvements in cardiac output, LV peak+dP/dt, LV fractional area of shortening and LV ejection fraction measured angiographically. Discontinuation of the signal resulted in a return of all functional parameters to baseline values. In cardiomyocytes isolated from dogs with chronic heart failure, application of the CCM signal resulted in improved shortening, rate of change of shortening and rate of change of relengthening suggesting that CCM application is associated with intrinsic improvement of cardiomyocyte function. The improvement in isolated cardiomyocyte function after application of the CCM signal was accompanied by an increase in the peak and integral of the Ca2+ transient suggesting modulation of calcium cycling by CCM application. In a limited number of normal dogs, intermittent chronic delivery of the CCM signal for up to 7 days showed chronic maintenance of LV functional improvement. In conclusion, pre-clinical results to date with the Impulse Dynamics CCM signal indicate that this non-pharmacologic therapeutic modality can provide short-term positive inotropic support to the failing heart and as such, may be a useful adjunct in the treatment of advanced heart failure. Additional, long-term studies in dogs with heart failure are needed to establish the safety and efficacy of this therapeutic modality for the chronic treatment of this disease syndrome.

Relation of left ventricular chamber shape in patients with low (≤40%) ejection fraction to severity of functional mitral regurgitation

Abstract In conclusion, the results of this study indicate that severity of functional MR in patients with low ejection fraction appears to be dictated primarily by increased sphericity of the left ventricle rather than by mitral annular dilatation or LV chamber enlargement.

Effects of the AT1-receptor antagonist eprosartan on the progression of left ventricular dysfunction in dogs with heart failure.

We examined the effects of eprosartan, an AT1 receptor antagonist, on the progression of left ventricular (LV) dysfunction and remodelling in dogs with heart failure (HF) produced by intracoronary microembolizations (LV ejection fraction, EF 30 to 40%). Dogs were randomized to 3 months of oral therapy with low‐dose eprosartan (600 mg once daily, n=8), high‐dose eprosartan (1200 mg once daily, n=8), or placebo (n=8). In the placebo group, LV end‐diastolic (EDV) and end‐systolic (ESV) volumes increased after 3 months (68±7 vs 82±9 ml, P<0.004, 43±1 vs 58±7 ml, P<0.003, respectively), and EF decreased (37±1 vs 29±1%, P<0.001). In dogs treated with low‐dose eprosartan, EF, EDV, and ESV remained unchanged over the course of therapy, whereas in dogs treated with high‐dose eprosartan, EF increased (38±1 vs 42±1%, P<0.004) and ESV decreased (41±1 vs 37±1 ml, P<0.006), Eprosartan also decreased interstitial fibrosis and cardiomyocyte hypertrophy. We conclude that eprosartan prevents progressive LV dysfunction and attenuates progressive LV remodelling in dogs with moderate HF and may be useful in treating patients with chronic HF.

Effects of pre-existing left ventricular hypertrophy on ventricular dysfunction and remodeling following myocardial infarction in rats

BACKGROUND Myocardial hypertrophy is a characteristic component of left ventricular (LV) remodeling that may, at least initially, have a beneficial effect on LV function following myocardial infarction (MI). In the present study, we examine the effects of pre-existing left ventricular hypertrophy (LVH) on LV function and chamber enlargement following MI in inbred Lewis rats. METHODS The one-kidney, one-clip model (1K1C) of hypertension was used to produce LVH. Four weeks after 1K1C, rats were randomized to left anterior descending coronary artery ligation (LVH + MI group, n = 8) or sham ligation (LVH group, n = 11). Another group of rats underwent sham 1K1C. Four weeks later, they were randomized to coronary ligation (MI group, n = 12) or sham ligation (Sham group, n = 12). LV end-diastolic pressure (EDP, mm Hg), end-diastolic volume (EDV, ml), end-systolic volume (ESV, ml) and ejection fraction (EF) (determined by angiography) were measured in all groups 2 months after MI. RESULTS LV EDP was 20 +/- 2 mm Hg in the LVH + MI group compared with 9 +/- 1 mm Hg in the MI group (p < 0.05). LV EDV and ESV were significantly greater with LVH + MI than with MI alone (EDV 0.90 +/- 0.03 vs 0.75 +/- 0.02 ml; ESV 0.68 +/- 0.02 vs 0.50 +/- 0.03 ml; p < 0.05). Pre-existing LVH resulted in a greater reduction in EF following MI (25 +/- 2% for LVH + MI vs 34 +/- 2% for MI alone; p < 0.05). CONCLUSIONS Pre-existing LVH is an important determinant of progressive LV dysfunction and remodeling following MI in Lewis inbred rats.