sildenafil-citrate and Mitral-Valve-Insufficiency

Ventricular remodelling describes structural changes in the left ventricle in response to chronic alterations in loading conditions, with three major patterns: concentric remodelling, when a pressure load leads to growth in cardiomyocyte thickness; eccentric hypertrophy, when a volume load produces myocyte lengthening; and myocardial infarction, an amalgam of patterns in which stretched and dilated infarcted tissue increases left-ventricular volume with a combined volume and pressure load on non-infarcted areas. Whether left-ventricular hypertrophy is adaptive or maladaptive is controversial, as suggested by patterns of signalling pathways, transgenic models, and clinical findings in aortic stenosis. The transition from apparently compensated hypertrophy to the failing heart indicates a changing balance between metalloproteinases and their inhibitors, effects of reactive oxygen species, and death-promoting and profibrotic neurohumoral responses. These processes are evasive therapeutic targets. Here, we discuss potential novel therapies for these disorders, including: sildenafil, an unexpected option for anti-transition therapy; surgery for increased sphericity caused by chronic volume overload of mitral regurgitation; an antifibrotic peptide to inhibit the fibrogenic effects of transforming growth factor beta; mechanical intervention in advanced heart failure; and stem-cell therapy.

Topics: Animals; Attitude of Health Personnel; Cardiomegaly; Humans; Mitral Valve Insufficiency; Models, Cardiovascular; Oxidative Stress; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents; Ventricular Remodeling

Myxomatous mitral valve degeneration (MMVD) causes an imbalance of sympathovagal activity resulted in poor cardiac outcomes. Phosphodiesterase-5 inhibitors have been revealed cardioprotective effect in patients with heart diseases. This study aimed to 1) compare the heart rate variability (HRV) between asymptomatic MMVD and healthy dogs and 2) assess long-term effects of sildenafil and enalapril on time- and frequency-domains analyzes. Thirty-four dogs with MMVD stage B1 or B2 and thirteen healthy dogs were recruited into the study. MMVD dogs were divided into 3 subgroups: control (n=13), sildenafil (n=12) and enalapril (n=9). HRV was analyzed from 1-hr Holter recording at baseline (D0) in all dogs and at 30, 90 and 180 days after treatment. The results showed that MMVD dogs had significant higher heart rate (HR), systemic blood pressures, the ratio of low to high frequency (LF/HF) and had significant decreased standard deviation of all normal to normal RR intervals (SDNN) and the percentage of the number of normal-to-normal sinus RR intervals with differences >50 msec computed over the entire recording (pNN50) when compared with healthy dogs (P<0.05). Neither time nor frequency domain parameters were different among subgroups of MMVD dogs at D0. After treatment with sildenafil for 90 days, both time- and frequency-domain parameters were significantly increased when compared with control and enalapril groups. This study demonstrated that sildenafil improves HRV in asymptomatic MMVD dogs suggesting that sildenafil should be used in the MMVD dogs to restore the sympathovagal balance.

Topics: Animals; Dog Diseases; Dogs; Female; Heart Rate; Male; Mitral Valve Insufficiency; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

Sildenafil is a selective phosphodiesterase-5 inhibitor that has been demonstrated to delay ventricular remodeling in humans and experimental animals. The aim of this prospective study was to assess the chronic effects of sildenafil administration on echocardiographic indices and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in dogs with naturally occurring, asymptomatic myxomatous mitral valve degeneration. Thirty client-owned dogs with ACVIM class B1 or B2 were enrolled. Dogs were randomly assigned to treatment (sildenafil 1-3 mg/kg, PO, BID for 180 days) or control groups. A total of 12 dogs completed the 180 days trial in the sildenafil group, whereas 10 dogs remained in control group. When comparing the difference from baseline values obtained over time between groups, the stroke volume (SV) at day 30 was significantly higher in the sildenafil group (P=0.038). The LA/Ao and the MR jet area were significantly lower beginning at day 30 (only MR jet area; P=0.006), day 90 (P=0.006 and P=0.027, respectively) and day 180 (P=0.029 and P=0.032, respectively). The 2D-LA was significantly lower at day 90 when compared with control group (P=0.028). The differences of NTproBNP from baseline were significantly lower when compared with control group at the same timepoint (D90, P=0.017 and D180, P=0.013). In conclusion, this study suggested that long-term treatment with sildenafil prevented aggravation of disease progression as suggested by several echocardiographic indices (i.e. SV, LA/Ao, MR jet area, 2D-LA) and reduced NTproBNP level at the indicated timepoints in dogs with asymptomatic mitral valve degeneration.

Topics: Animals; Disease Progression; Dog Diseases; Dogs; Echocardiography; Electrocardiography; Female; Male; Mitral Valve Insufficiency; Natriuretic Peptide, Brain; Phosphodiesterase 5 Inhibitors; Prospective Studies; Radiography; Sildenafil Citrate; Time Factors

We tested the hypothesis that chronic treatment with sildenafil attenuates left ventricular (LV) remodeling and prevents exercise intolerance in chronic mitral regurgitation (MR).. MR was created in Sprague-Dawley rats by making a hole on the mitral leaflet. Two weeks after MR creation, MR and LV dilatation were confirmed by echocardiography, and rats were randomly assigned to sildenafil treatment (MR+sildenafil group; 50 mg/kg PO twice a day; n=16) or normal saline only (MR group; n=16) and continued for 4 months. Sixteen sham rats were compared with MR rats. After 4 months, LV size was smaller in the MR+sildenafil compared with the MR group (LV end-systolic dimension, 4.7±0.3 for sham versus 5.9±0.3 for MR+sildenafil versus 7.4±0.5 mm for MR; P<0.05; LV end-diastolic dimension, 8.3±0.4 versus 10.5±0.2 versus 11.7±0.61 mm, respectively; P<0.05). LV ejection fraction was greater in the MR+sildenafil group than in the MR group (70.2±2.2 for sham versus 67.0±4.2 for MR+sildenafil versus 58.9±2.5 for MR; P=0.01). Serial treadmill test revealed that exercise capacity was reduced in the MR but not in the MR+sildenafil group. Transcriptional profiling of cardiac apical tissues revealed that gene sets related to inflammatory response, DNA damage response, cell cycle checkpoint, and cellular signaling pathways were significantly enriched by genes with reciprocal changes. Pathological analysis showed that perivascular fibrosis was more prominent in the MR than in the MR+sildenafil group and that the percentage of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells was 2-fold greater in the MR compared with the MR+sildenafil group.. Sildenafil significantly attenuates LV remodeling and prevents exercise intolerance in a rat model of chronic MR. This benefit may be associated with the antiapoptotic, anti-inflammatory effects of sildenafil.

Topics: Animals; Chronic Disease; Disease Models, Animal; Male; Mitral Valve Insufficiency; Physical Conditioning, Animal; Physical Endurance; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Survival Analysis; Time Factors; Ventricular Remodeling

Topics: Animals; Disease Models, Animal; Male; Mitral Valve Insufficiency; Physical Conditioning, Animal; Physical Endurance; Piperazines; Purines; Sildenafil Citrate; Sulfones; Ventricular Remodeling

Heart failure is a condition that affects nearly 5 million people in the United States and costs the nation an estimated $35 billion a year. Although common, the condition presents treating clinicians with real challenges. There currently are few effective therapies for people with acute decompensated disease. As part of the National Heart Lung and Blood Institute-funded Heart Failure Network, Minnesota researchers are attempting to change this. This article describes the work of the Heart Failure Network and several Minnesota-designed protocols that are being tested, including one that's looking at 2 different treatment strategies for patients hospitalized with acute decompensated heart failure who go on to develop poor renal function and another that will evaluate the use of sildenafil (Viagra) for patients with heart failure and preserved left ventricular systolic function.

Topics: Diuretics; Heart Failure; Hemofiltration; Humans; Minnesota; Mitral Valve Insufficiency; National Heart, Lung, and Blood Institute (U.S.); Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; United States; Vasodilator Agents

Pulmonary hypertension remains a major cause of morbidity after cardiac surgery, although inhaled nitric oxide (iNO) was shown to have clinical benefit. Some patients are dependent on iNO, increasing the length of hospital stay. The authors report a case of a girl, nine years old (17 kg), with mitral insufficiency, atrial septal defect and pulmonary hypertension (80% of systemic pressure). Following cardiac surgery, pulmonary hypertension persisted and iNO could not be withdrawn. Sildenafil was administered orally (1,5mg x kg(-1), every 4 h) at the 15th postoperative day and iNO could be withdrawn within 24h with clinical improvement.

Topics: Administration, Inhalation; Cardiac Surgical Procedures; Child; Female; Heart Septal Defects, Atrial; Humans; Hypertension, Pulmonary; Mitral Valve Insufficiency; Nitric Oxide; Piperazines; Postoperative Complications; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents