**6. Clinical use of PDE-5 inhibitors in patients with heart failure**

Following years of basic research examining the cardioprotective effects of PDE-5 inhibitors against ischemia, a recent study by Guazzi et al. demonstrated that sildenafil improves LV diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart

Phosphodiesterase-5 Inhibitors Improve Left Ventricular Function in Failing Hearts 111

compared with placebo (P<0.01). Additionally, diastolic measures of LV function demonstrated systematic and sustained improvement after both 6 months and 1 year of sildenafil treatment. The transmitral E/A ratio, isovolumic relaxation time, and both lateral and septal E/E′ decreased from baseline through 12 months (all P<0.01), which is indicative of an improvement in LV diastolic function and a decrease in LV filling pressure. Furthermore, septal T E-E′ was significantly reduced at 6 and 12 months of sildenafil treatment (P<0.01). All these changes were in agreement with the observed reverse remodeling on LAVI, which is viewed as morphological expression of LV end-diastolic pressure (Lester et al., 2008). Changes observed at 6 months and 1 year after sildenafil were

With the advancement in the management of patients with cardiovascular disease and improvement in survival following cardiovascular events, the incidence of heart failure, especially in patients of age 65 and older is increasing. Using state-of-the-art echocardiography, we and others have demonstrated that treatment with PDE-5 inhibitors improve LV function in various models of myocardial dysfunction and heart failure. These studies suggest that PDE-5 inhibitors are immensely promising for further development as novel drug therapies for myocardial infarction, LV hypertrophy and dysfunction, doxorubicin-induced cardiotoxicity, and heart failure. Clinical studies of sildenafil on heart failure patients have reported improved exercise capacity, coupled with reduced pulmonary vascular resistance and better endothelial function (Lewis et al., 2007; Guazzi et al., 2007). Sildenafil also preserved LV function in patients with heart failure due to various etiologies (Guazzi et al., 2011). Several other studies indicated that PDE-5 inhibition with sildenafil has a therapeutic promise for stroke, neurodegenerative diseases and potentially other circulatory disorders (reviewed in Kukreja et al., 2007; Kukreja et al., 2011a; Kukreja et al. 2011b). These drugs may not only delay or reduce the pathological damage or defects in various vital organs, but also improve the overall well-being and quality of life in patients.

This work was supported by grants from the National Institutes of Health (HL51045, HL79424 and HL93685) to Rakesh C. Kukreja and a National Scientist Development Grant

Adamo CM. Phosphodiesterases as Drug Targets, Evaluation of the Therapeutic Utility of

Adamo CM, Dai DF, Percival JM, Minami E, Willis MS, Patrucco E, Froehner SC, Beavo JA.

Anversa, P, Li P, Zhang X, Olivetti G, Capasso JM. Ischaemic myocardial injury and

muscular dystrophy. *Proc Natl Acad Sci U S A.* 2010; 107:19079-83.

ventricular remodelling. *Cardiovasc Res.* 1993; 27:145-57.

Phosphodiesterase 5A Inhibition in the mdx Mouse Model of Duchenne Muscular Dystrophy, eds Schmidt HHW, Hofmann F, Stasch JP (Springer-Verlag, New York).

Sildenafil reverses cardiac dysfunction in the mdx mouse model of Duchenne

from the American Heart Association (10SDG3770011) to Fadi N. Salloum.

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significantly different compared with the placebo group (P<0.01).

**7. Concluding remarks** 

**8. Acknowledgment** 

**9. References** 

failure (Guazzi et al., 2011). The study primarily focused on the effects of chronic PDE-5 inhibition on LV diastolic function and cardiac chamber remodeling, providing the first human evidence that PDE-5 inhibition can be beneficial for improving the diastolic and structural properties of the failing LV. Transthoracic echocardiography was performed using IE33, Philips ultrasound machine, equipped with a software for tissue Doppler (TD), using a 2.5- to 5.0-MHz probe (S5). Standard M-mode, 2D, and Doppler blood flow measurements were performed according to the current American Society of Echocardiography Guidelines (Quiñones et al., 2002). Chamber dimensions were obtained using standard procedures including left atrial volume index (LAVI) and LV mass index (LVMI) (Devereux & Reichek, 1977). Septal and posterior wall thickness, LA, and LV end-systolic and end-diastolic dimensions were obtained from the parasternal long-axis view. LVEF, end-diastolic volume index (LVEDVI), and end-systolic volume index were evaluated with the Simpson method.

Interestingly, E/E′, a variable repeatedly found related to LV filling pressures in a variety of left-sided cardiac disorders (Lester et al., 2008), significantly decreased at 6 months and 1 year of active treatment (Figure 9). Additional study findings that support the hypothesis that PDE-5 inhibition may represent a novel and viable therapeutic strategy for improving LV relaxation were the significant shortening in both lateral and septal T E-E′, a Dopplerderived index of LV relaxation performance validated against invasively measured negative dP/dT22, and the reverse remodeling effect on LV mass. Moreover, over 12 months, LAVI, LVEDV, and LVMI were unchanged in the placebo group and decreased in the active treatment group, which suggests reverse remodeling with sildenafil involving both the ventricle and the atrium. Over the same time period in the sildenafil group, there was a progressive increase in mean LVEF, from 29.5% at baseline to 34.9% and 36.3% at 6 and 12 months, respectively (P<0.01). Changes observed with sildenafil were significantly different

Fig. 9. Sildenafil significantly decreased E/E′ at 6 months and 1 year of active treatment in patients with stable systolic heart failure

compared with placebo (P<0.01). Additionally, diastolic measures of LV function demonstrated systematic and sustained improvement after both 6 months and 1 year of sildenafil treatment. The transmitral E/A ratio, isovolumic relaxation time, and both lateral and septal E/E′ decreased from baseline through 12 months (all P<0.01), which is indicative of an improvement in LV diastolic function and a decrease in LV filling pressure. Furthermore, septal T E-E′ was significantly reduced at 6 and 12 months of sildenafil treatment (P<0.01). All these changes were in agreement with the observed reverse remodeling on LAVI, which is viewed as morphological expression of LV end-diastolic pressure (Lester et al., 2008). Changes observed at 6 months and 1 year after sildenafil were significantly different compared with the placebo group (P<0.01).
