Sildenafil Boosts the Heart's Performance, Too

EDMONTON, Alberta, July 12 -- Phosphodiesterase type 5 (PDE5) drugs, such as sildenafil (Viagra), may improve right ventricular contractility in hearts with right ventricular hypertrophy, an unexpected benefit that looks promising for treatment of right ventricular heart failure.
Although it was thought that PDE5 was not expressed in the heart, Evangelos D. Michelakis, M.D., of the University of Alberta, and colleagues discovered that levels of the protein were high in diseased right ventricles of human hearts.
Testing PDE5 inhibition in rats with right ventricular hypertrophy, they found it improved right ventricle contractility and decreased afterload without significantly affecting systemic hemodynamics, they reported online in the journal Circulation.
Because there are no treatments available for patients with a failing right ventricle, they said, "our findings might have direct implications for the growing patient population with right ventricle dysfunction, including patients with pulmonary arterial hypertension, chronic thromboembolic disease, or congenital heart disease, and those after lung transplantation."
The researchers examined cardiac expression of PDE5 in hypertrophied right ventricles using human heart samples from biopsy or surgical resection from nine patients.
Specimens were from seven patients with right ventricle hypertrophy, one patient with left ventricle hypertrophy but a normal right ventricle, and one patient with normal left and right ventricles.
In tissue from normal human left and right ventricles, as expected from previous studies, the investigators found PDE5 expressed only in the coronary artery media and not in the myocardium.
But in all the hypertrophied right ventricles, PDE5 was markedly upregulated on immunohistochemistry. The difference was confirmed in a normal and a hypertrophied sample with an immunoblot.
The same pattern was seen in tissue from the patient with a hypertrophied left ventricle but normal right ventricle. PDE5 expression was upregulated only in the left ventricle myocardium.
This "suggests that the PDE5 upregulation is restricted only to the pressure-overloaded chamber and is likely not induced by circulating factors," the researchers wrote.
Because right ventricle hypertrophy patients do not have PDE5 expressed in the left ventricle, "PDE5 inhibition should not affect the left ventricle myocardium," the researchers noted. "In that sense, PDE5 inhibitors are truly right ventricle hypertrophy chamber specific."
Likewise, the researchers found significantly higher levels of PDE5 messenger RNA in the damaged right ventricle myocardium than in normal tissue. Levels were similar between groups in the coronary arteries.
The researchers reproduced these results in a rat model of pulmonary arterial hypertension and right ventricular hypertrophy produced by intraperitoneal injection of monocrotaline.
To see if their findings would be physiologically significant, Dr. Michelakis and colleagues mimicked clinical conditions by feeding sildenafil to rats with normal hearts and those with right ventricle hypertrophy.
To exclude confounding factors, the researchers looked at right ventricle contractility while recording right ventricle pressure, occluding the pulmonary artery afterload, and keeping the preload constant in an isolated perfused heart preparation.
Contractile pressure did not change in hearts from normal sildenafil-treated rats compared with nontreated controls. But, hypertrophied right ventricles from sildenafil-treated rats with had a significant increase in baseline developed pressure and maximum rate of change in right ventricular pressure (dP/dt) compared with untreated controls with right ventricle hypertrophy in the isolated perfused heart model.
Myocardial cell shortening showed the same improvement in contractility with PDE5 inhibition.
Further experiments in human heart tissue showed that sildenafil increased cyclic guanosine monophosphate (cGMP) levels and cyclic adenosine monophosphate (cAMP) only in hypertrophied right ventricle tissue but not in normal tissue.
The researchers cautioned that most patients in the study did not have overt right ventricular failure nor did the rats, so the results cannot be extrapolated for patients with advanced disease or dilated or thin-walled right ventricles.
Also, they said, "more work is needed to study the long-term effect of PDE5 inhibitors in both compensated and decompensated right ventricular disease."
Nevertheless, they concluded, "our findings have immediate clinical applications. PDE5 inhibition might be a new means of enhancing right ventricular function, which has repeatedly been shown to be a critical predictor of functional status in many cardiovascular diseases."
Dr. Michelakis reported receiving consultant fees from Pfizer and grants from the Canadian Institutes of Health Research, Alberta Heart and Stroke Foundation, Alberta Heritage Foundation for Medical Research, Canadian Foundation for Innovation, and Canada Research Chairs program. Another researcher was funded by the Canadian Institutes of Health Research, Alberta Heritage Foundation for Medical Research, and University of Alberta.Primary source: CirculationSource reference: Nagendran J, et al "Phosphodiesterase Type 5 Is Highly Expressed in the Hypertrophied Human Right Ventricle, and Acute Inhibition of Phosphodiesterase Type 5 Improves Contractility" Circulation. 2007; 116: DOI:10.1161/CIRCULATIONAHA.106.655266.