sildenafil-citrate and Ventricular-Dysfunction

Right ventricular (RV) dysfunction following left ventricular (LV) failure is associated with poor prognosis. RV remodeling is thought initiated by the increase in the afterload of RV due to secondary pulmonary hypertension (PH) to impaired LV function; however, RV molecular changes might occur in earlier stages of the disease. cGMP (cyclic guanosine monophosphate)-phosphodiesterase 5 (PDE5) inhibitors, widely used to treat PH through their pulmonary vasorelaxation properties, have shown direct cardiac benefits, but their impacts on the RV in LV diseases are not fully determined. Here we show that RV molecular alterations occur early in the absence of RV hemodynamic changes during LV pressure-overload and are ameliorated by PDE5 inhibition. Two-day moderate LV pressure-overload (transverse aortic constriction) neither altered RV pressure/ function nor RV weight in mice, while it induced only mild LV hypertrophy. Importantly, pathological molecular features were already induced in the RV free wall myocardium, including up-regulation of gene markers for hypertrophy and inflammation, and activation of extracellular signal-regulated kinase (ERK) and calcineurin. Concomitant PDE5 inhibition (sildenafil) prevented induction of such pathological genes and activation of ERK and calcineurin in the RV as well as in the LV. Importantly, dexamethasone also prevented these RV molecular changes, similarly to sildenafil treatment. These results suggest the contributory role of inflammation to the early pathological interventricular interaction between RV and LV. The current study provides the first evidence for the novel early molecular cross-talk between RV and LV, preceding RV hemodynamic changes in LV disease, and supports the therapeutic strategy of enhancing cGMP signaling pathway to treat heart diseases.

Topics: Animals; Calcineurin; Cardiomegaly; Cardiovascular Agents; Dexamethasone; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Heart Ventricles; Hemodynamics; Macrophages; Male; Mice, Inbred C57BL; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Ventricular Dysfunction; Ventricular Function, Left; Ventricular Function, Right; Ventricular Pressure

To accurately verify the effect of Sildenafil on blood pressure (BP) and heart rate (HR) in individuals with Chagasic myocardiopathy (CMC) and severe systolic ventricular dysfunction (EF<40%) submitted to physical activity.. Twelve men with ejection fractions <40% and CMC confirmed by a serological test were assessed. The six-minute walk test (6MWT) was performed before and after administration of 50 mg of Sildenafil, with a 30 minute interval. Heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure were taken and compared before and after each 6MWT. For statistical analysis purposes, the study was divided into four stages: before the 6MWT and administration of Sildenafil (S1); after the 6MWT but before the administration of Sildenafil (S2); after the administration of Sildenafil but before the 6MWT (S3); and after the administration of Sildenafil and the 6MWT (S4).. Participant ages ranged from 47 to 68 years (57.6 +/- 6.4). SBP and DBP after the 6MWT and the administration of Sildenafil (S4) were lower than before taking the drug (S2): 134.2 +/- 15.1 versus 125.5 +/- 14.0 and 88.4 +/- 12.4 versus 83.0 +/- 10.8, respectively. None of the patients reported any symptoms during the 6MWT. There were no differences in the distances walked during the 6MWT before or after taking Sildenafil (487.5+/-15.22 versus 505.3+/-18.45 meters, respectively)-p=0.056, or in HR (before Sildenafil 75.5 +/- 8.79 and 96.8 +/- 10.36 bpm and after 77.1 +/- 9.81 and 96.1 +/- 12.97 bpm).. A significant reduction in BP after physical activity while using Sildenafil was observed. However, during the six-minute walk test, the patients did not report any symptoms, indicating that this effect is not sufficient to cause clinical manifestations in CMC and heart failure patients.

Topics: Aged; Blood Pressure; Chagas Cardiomyopathy; Chi-Square Distribution; Exercise Test; Heart Rate; Humans; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Systole; Time Factors; Vasodilator Agents; Ventricular Dysfunction