doi: 10.1111/j.1751-7133.2008.00026.

REVIEW PAPER

Treating Heart Failure With Sildenal

ildenal is a selective inhibitor of type 5 phosphodiesterase (PDE5), the main phosphodiesterase (PDE) isoform responsible for hydrolysis of intracellular cyclic guanosine monophosphate (cGMP) in the pulmonary vasculature. It has been successfully used to treat erectile dysfunction and has been shown to improve exercise capacity and decrease pulmonary vascular resistance at rest in patients with pulmonary arterial hypertension and normal left ventricular (LV) function. This review will summarize the data on sildenal treatment for heart failure (HF) patients and will explain the mechanisms of its benecial effects in this syndrome.

Sildenal is a selective inhibitor of type 5 phosphodiesterase, the main phosphodiesterase isoform responsible for hydrolysis of intracellular cyclic guanosine monophosphate in the pulmonary vasculature. It improves exercise capacity and quality of life in patients with systolic heart failure, especially in those who develop secondary pulmonary hypertension. It improves peak oxygen consumption, reduces minute ventilation carbon dioxide output slope, and acts as a selective pulmonary vasodilator during rest and exercise in patients with heart failure and pulmonary hypertension. It improves ow-mediated maximal dilatation, ergoreex on ventilation, and breathlessness both after 3 and 6 months of treatment. Sildenal, by improving endothelial activity and muscle perfusion, improves signaling and ventilatory efciencies, potentially indicating a novel approach in the therapeutic management of heart failure. Congest Heart Fail. 2009;15:181185. 2009 Wiley Periodicals, Inc. Arnon Blum, MD From the Department of Internal Medicine, Baruch-Padeh Poria Medical Center, Lower Galilee, Israel Address for correspondence: Arnon Blum, MD, Department of Internal Medicine, Baruch-Padeh Poria Medical Center, Lower Galilee 15208, Israel E-mail: navablum@hotmail.com Manuscript received May 21, 2008; revised September 6, 2008; accepted September 24, 2008

Background
Pulmonary hypertension is present in 68% to 78% of patients with severe LV systolic HF, commonly associated with right ventricular (RV) dysfunction.13 Apparently, patients with LV dysfunction are dependent on pulmonary vascular resistance and RV performance, parameters that are important determinants of exercise capacity35 and prognosis.1,69 Abnormal systemic vascular tone is another hallmark of HF that decreases skeletal muscle perfusion and increases systemic vascular resistance.10,11 Administration of inhaled nitric oxide (NO) (that has been proved to selectively dilate the pulmonary vasculature) to patients with LV systolic dysfunction reduced the pulmonary vascular resistance and increased the cardiac index of these patients without affecting the systemic arterial pressure.12,13 Inhaled NO increased the exercise capacity and the RV ejection fraction of HF patients who had pulmonary hypertension.14 The problem with inhaled
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NO, however, is that it has a very short half-life and cannot be continuously administered to ambulatory patients. An alternative approach was to inhibit cGMP (the second messenger of NO in vascular smooth muscle cell breakdown) through inhibition of PDEs. Sildenal is a selective inhibitor of PDE5, the important isoform responsible for hydrolysis of cGMP in the lungs.15 Sildenal has been shown to effectively dilate the pulmonary vasculature (as effective as NO)16,17 in patients with primary or secondary pulmonary hypertension,18 to lower resting pulmonary vascular resistance and pulmonary capillary wedge pressure, and to increase cardiac index without affecting the systemic arterial pressure.19 In this review, I will summarize the clinical studies that examined the effects of sildenal as an adjunctive treatment for patients with severe HF (Table).

Effects of Sildenal on Exercise Capacity in Patients With Systolic HF

In a randomized, double blind, placebocontrolled study, 34 patients with New York Heart Association (NYHA) HF class II through IV and secondary pulmonary hypertension were enrolled. They were randomly assigned to receive sildenal or placebo 3 times daily for 12 weeks.20 Those who received sildenal improved their exercise capacity, measured by peak VO2 and 6-minute walk distance. Also improved were their quality of life and pulmonary vascular resistance at rest and during exercise. Sildenal was well tolerated, and those who took it had fewer hospital admissions compared with the placebo group. The improvement in exercise capacity was secondary to the increase in cardiac output, and there are several possible mechanisms for that positive change. One possible explanation is the
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improved RV systolic function due to afterload reduction (because of the reduced pulmonary vascular resistance). Another explanation could be an augmentation of the cardiac output through increased LV lling, even though no LV end-diastolic volume change was observed. Still, it could be because a trend toward a decrease in systemic vascular resistance was observed in this study.20 Several researchers suggested that there could be an increase in RV contractility,21 but previous animal and human studies had shown that PDE5 inhibition in patients with HF or in animal models with HF did not affect myocardial contractility.19,22 What Are the Practical Implications? HF patients with RV dysfunction have an increased mortality (2-fold) compared with HF patients with preserved RV function.23,24 Several medical approaches could not demonstrate a benecial effect with this population: bosantan (endothelin receptor blocker) treatment caused uid retention and did not improve HF symptoms,25 and epoprostenol (the synthetic form of prostacyclin) treatment was associated with increased mortality.26 There is only one exception to these failed trialsthe combination of isosorbide dinitrate and hydralazine in black individuals with HF.27 In a way, sildenal and isosorbide dinitrate share some signaling pathways involving the intracellular second messenger cGMP. The great advantage of sildenal, however, is the lack of tachyphylaxis that is commonly observed with long-term nitrate therapy.18

response to carbon dioxide (CO2) output in HF patients with NYHA HF class II.10,11 But what is the mechanism behind these effects? In order to answer this, the exercise hemodynamics and peripheral oxygen extraction need to be studied and measured. Measurements of these parameters will provide some insight into the mechanisms by which sildenal improves exercise capacity in HF patients. Effects on Pulmonary Arterial Hypertension. Thirteen patients with HF and NYHA class III took part in a study after optimizing their medical therapy. None had any underlying pulmonary disease however, all had elevated resting pulmonary arterial pressure and pulmonary capillary wedge pressures and their cardiac index was depressed. Exercise capacity was depressed as well.31 All patients received sildenal and all tolerated it without hypotension, facial ushing, or vision changes. Measurements were performed 60 minutes after administration of 50 mg of oral sildenal. Sildenal reduced resting pulmonary arterial pressure, systemic vascular resistance, and pulmonary vascular resistance. It also increased resting and exercise cardiac index without altering mean arterial pressure. During exercise, sildenal reduced exercise pulmonary arterial pressure, pulmonary vascular resistance, and the ratio between pulmonary vascular resistance and systemic vascular resistance, which indicates a selective pulmonary vasodilator effect with exercise. Is There a Selective Effect in Favor of Patients With Secondary Pulmonary Hypertension? Interestingly, sildenal affected only patients who had pulmonary hypertension. However, sildenal had no effect on hemodynamic parameters in the group of patients without pulmonary hypertension at rest.31 The reduction in pulmonary vascular resistance and the ratio between pulmonary vascular resistance and systolic vascular resistance was greater in HF patients with pulmonary hypertension than in the group of patients without pulmonary

hypertension. In the group of patients with HF and pulmonary hypertension, the RV ejection fraction increased at rest and during exercise, but no difference in RV performance was observed in the group of HF patients without pulmonary hypertension. This study has shown that a single dose of sildenal (50 mg) can improve exercise capacity and hemodynamics through pulmonary vasodilatation in patients with chronic systolic HF. Within 60 minutes, sildenal improved exercise capacity, reduced pulmonary arterial pressure and pulmonary vascular resistance, and increased the cardiac index during exercise, altogether with increasing the RV ejection fraction at rest and with exercise and improving ventilatory efciency. These effects were more dominant and signicant among HF patients with secondary pulmonary hypertension.31

Effects of Sildenal on Ergoreex

Chronic HF is characterized by fatigue and dyspnea, accompanied by reduced exercise performance and increased ventilatory response to exertion. Why do people with HF feel short of breath? Why are they tired so much? Partial explanation can be found in a relatively new phenomenon called ergoreex. Ergoreex is a reex that originates from group III and IV neural afferents located in the skeletal muscle. They are also called ergoreceptors and are composed of 2 types: the metaboreceptors (sensitive to metabolic byproducts) and mechanoreceptors (sensitive to changes in limbs and joints).32 This reex causes an increase in autonomic outow and ventilation and contributes to the sensation of breathlessness, reduction in exercise capability, and whole symptomatic deterioration of the HF syndrome in HF patients.3234 What about the endothelium? Does it play any role in this newly dened reex? We know that HF patients experience severe endothelial dysfunction,28,35,36 and it could be one of the factors that overactivates the ergoreex in patients with HF. In order to study this possibility, 16 patients with chronic HF and 16 healthy controls were
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Effects of Sildenal on Exercise Hemodynamics

Increased systemic vascular resistance and diminished skeletal muscle perfusion are characteristic of HF. Sildenal has been shown to improve endothelium-dependent ow-mediated brachial artery dilation in HF patients.28,29 It also improves skeletal muscle perfusion and anaerobic metabolism during exercise in this population.30 Sildenal has been shown to increase peak VO2 and increase the efciency of the ventilatory
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studied, before and after taking sildenal 50 mg (or placebo), measuring their ergoreex, ow-mediated brachial artery dilation, and during maximal exertion; the slope of ventilation to CO2 production; and the ratio of change in oxygen uptake vs work rate. Measurements that were performed in patients with HF 60 minutes after sildenal intake have shown that there were no signicant changes in heart rate and systemic arterial pressure, but there was a signicant decrease in systolic pulmonary artery pressure, ergoreex effect on ventilation, and a signicant increase in brachial artery ow-mediated vasodilatation and peak oxygen consumption (VO2). In patients with HF, the baseline brachial artery ow-mediated diameter was inversely related to the baseline ergoreex component of the ventilatory response to handgrip. The changes in ow-mediated diameter after sildenal were inversely related with changes in ergoreex. All the effects that were measured with sildenal disappeared after 24 hours.37 This study demonstrated that in patients with HF, inhibition of PDE5 attenuates the peripheral stimulus to exercise hyperventilation (ergoreex), which is associated with an increased brachial artery ow-mediated diameter and a reduced steepness of the VE VCO2 slope, demonstrating an improved ventilatory efciency. What is the Sensation of Breathlessness? It is observed as an increase in the slope of the ratio of ventilation to CO2 production. Hyperventilation may help in maintaining normal alveolar oxygen tension and accelerates exhaustion of the ventilatory reserve with less exercise capability. Possible mechanisms of hyperventilation include hypoperfusion of the ventilating lung, enlarged dead space of the lung, bicarbonate buffering of lactic acid accumulation, pulmonary interstitial space distension and j receptor activation, abnormal drive from the reexogenic areas of the cardiovascular system,11 skeletal muscle oversignaling, and raised passage of uid from the lung intravascular to the interstitial phase because of an excessive
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increase of the pulmonary capillary pressure on exertion. The improvement in exercise pulmonary hemodynamics, cardiac output, and peripheral perfusionall caused by sildenalcould attenuate many of these disorders, augment exercise capacity, and reduce hyperventilation. Reduction in pulmonary pressure and vascular resistance lead to improved ventricular ejection fraction, increased cardiac output, enhanced exercise performance,15 and shortened diffusion path between alveoli and capillaries because of diminished uid ux transition into the alveolar interstitial space.11 It seems that NO plays an important role in HF and by enhancing its availability through PDE5 inhibition, the endothelium-dependent ow-mediated dilatation is improved, as well as the perfusion in skeletal muscles during exercise.38 These effects may lead to attenuation of an exaggerated chemoreex-mediated ventilatory drive during exercise and in the observed improvement in ventilatory efciency. It has been shown that PDE5 inhibition can restore this mechanism and temper dyspnea through this peripheral effect on peripheral blood vessels.37 To summarize, it is possible that the endothelial dysfunction and lack of NO bioavailability observed in HF patients, together with the deprived exercising muscle and the overstimulation of neural afferents located in the skeletal muscles, emphasize the exercise ergoreex and affect patients ventilatory reactions and symptoms. In this patient population, sildenal potentiates the NO availability and efcacy and modulates exercise muscle signaling and reex neurogenic vasoconstriction, thus improving vascular responsiveness and the ventilatory efciency.

and those with erectile dysfunction. In order to study the long-term effects of sildenal on patients with chronic HF, 46 patients (23 patients in each group) with HF were randomly assigned to placebo or sildenal (50 mg twice daily), in addition to their current medications. The treatment was given for 6 months, with assessment at 3 months and at 6 months. The assessment included endothelial function by brachial artery ow-mediated dilatation, cardiopulmonary exercise testing, and ergoreex responses. Patients who were receiving sildenal (but none of the patients getting placebo) had a signicant reduction in systolic pulmonary artery pressure, a reduction in ergoreex effect on ventilation, a reduction in ventilation to CO2 production slope, and in breathlessness at 3 and 6 months of follow-up. All HF patients who received sildenal had increased endothelial function (owmediated dilatation), peak VO2, and the ratio of VO2 to work rate at 3 and 6 months of follow-up. In this group, a signicant correlation was found at 3 and 6 months between changes in owmediated diameter (NO-dependent vasodilatation) and those in ergoreex. Changes in ergoreex correlated with those in peak VO2 and the ratio between ventilation and CO2 production.39 Clinical Implications and Concerns. Sildenal was given orally at 50-mg doses (once, twice, and 3 times a day) in different clinical trials in patients with HF. No side effects were observed in any of the trials at any dosage given. The main concern was that patients with HF were getting different vasodilators, and that sildenal would cause hypotension and its consequences. However, no such event had happened in the different groups of patients. Further studies are needed to address different questions, such as what the effectiveness of sildenal is on different clinical classes of HF patients and whether it has the same effect on HF patients without pulmonary hypertension as it does on patients with different degrees of pulmonary hypertension.
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Long-Term Management of HF Patients

Unlike NO that has a very short halflife as a gaseous solution and is quite difcult to be used practically as a maintenance therapy, sildenal is more pharmaceutically stable and can be used for months with benecial effects for patients with pulmonary hypertension

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Table. Clinical Trials Studying Sildenal in Heart Failure

DESIGN Effects on exercise capacity 34 HF Patients (class IIIV) with secondary PH Sildenal vs placebo (50 mg 3 times daily for 12 weeks) Effects on exercise hemodynamics31 13 Patients (class III) with secondary PH Measurements were taken 60 minutes after 50 mg of oral sildenal Effects on ergoreex37 16 HF Patients vs 16 healthy controls Before and 60 minutes after oral sildenal 50 mg Long-term effects39 46 HF Patients (26 in a group) Sildenal 50 mg 2 times daily or placebo for 6 months Assessment at 3 months and 6 months
20

FINDINGS Exercise capacity Quality of life Pulmonary artery resistance at rest and during exercise Resting and exercise pulmonary artery pressure Systemic vascular resistance Pulmonary vascular resistance Cardiac index Right ventricular function at rest and during exercise In patients with HF: No change in heart rate or systemic arterial pressure Pulmonary artery pressure Ergoreex on ventilation Brachial ow-mediated vasodilatation Only patients who received sildenal Pulmonary arterial pressure Ergoreex on ventilation Brachial ow-mediated diameter Peak oxygen

LIMITATIONS Only patients with secondary PH

Only patients with secondary PH

All benecial effects were reversed after 24 hours

Abbreviations: HF, heart failure; PH, pulmonary hypertension. indicates increased; decreased.

Another critical question is whether sildenal can stop the progression of HF, or maybe even reverse the clinical route. In order to answer these questions, larger and longer clinical trials should be performed with different doses of sildenal and for different periods of time.

Conclusions
NO is an important mediator for vascular homeostasis and plays an REFERENCES
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