omapatrilat and Hypertrophy--Left-Ventricular

Left ventricular hypertrophy (LVH) in patients with hypertension is associated with an increased risk for many cardiovascular events and predicts a higher mortality rate. The pathogenesis of LVH is complicated. In addition to the hemodynamic burden (pressure or volume overload) and demographic factors, several trophic humoral factors, such as angiotensin II, aldosterone, endothelin, leptin, and catecholamines, may also contribute to the development and progression of LVH. Effective antihypertensive therapy can reverse LVH as well as prevent its development. Regression of LVH decreases subsequent cardiovascular morbidity and mortality. The commonly used drugs have various effects on LVH. Angiotensin receptor blockers and angiotensin-converting enzyme inhibitors seem most effective. Several new agents, including direct antifibrotic drugs, aldosterone blockade, vasopeptidase inhibitors, and endothelin receptor antagonists that more specifically target the underlying pathogenesis of LVH may provide us with innovative approaches to treat LVH.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Endothelin Receptor Antagonists; Humans; Hypertension; Hypertrophy, Left Ventricular; Mineralocorticoid Receptor Antagonists; ortho-Aminobenzoates; Protease Inhibitors; Pyridines; Thiazepines

Angiotensin-converting enzyme (ACE) inhibition attenuates ventricular remodeling and improves ventricular function in heart failure patients. Vasopeptidase inhibition has shown similar effects in experimental models.. The OVERTURE echocardiographic study was designed to test the hypothesis that the vasopeptidase inhibitor omapatrilat would attenuate ventricular remodeling and improve ventricular function to a greater extent than an ACE inhibitor.. Three hundred twenty-one patients with heart failure (New York Heart Association class > or = 2) were included in the OVERTURE echocardiographic substudy and were randomized to receive enalapril (10 mg twice a day) or omapatrilat (40 mg every day). Echocardiograms were performed at baseline and at 1 year (n = 214). Left ventricular size was estimated by summation of ventricular areas in apical and short-axis views and by calculation of ventricular volumes. Ejection fraction was calculated from ventricular volumes.. Combined diastolic and systolic areas and volumes decreased significantly (mean diastolic area change -8.36 cm2, 95% CI -9.4 to -7.3 cm2; mean systolic change -8.4 cm2, 95% CI -9.5 to -7.3 cm2), and ejection fractions increased significantly (3.6%, 95% CI 2.6% to 4.6%) in both treatment groups from baseline to 1 year. There were no differences in the magnitude of improvement in ventricular size or function based on treatment assignment. Patients who died or were hospitalized for heart failure subsequent to the final assessment demonstrated the least degree of reverse remodeling.. Ventricular size and function improved similarly after 1 year with ACE or vasopeptidase inhibition in patients with heart failure. Reverse remodeling was associated with improved outcome.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Cohort Studies; Enalapril; Female; Heart Failure; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Neprilysin; Organ Size; Proportional Hazards Models; Protease Inhibitors; Pyridines; Reproducibility of Results; Stroke Volume; Survival Analysis; Thiazepines; Treatment Outcome; Ultrasonography; Ventricular Remodeling

Topics: Adenosine; Angioplasty, Balloon, Coronary; Anti-Arrhythmia Agents; Antihypertensive Agents; Atherectomy, Coronary; Atrial Fibrillation; Azithromycin; Chlamydophila Infections; Coronary Disease; Defibrillators, Implantable; Double-Blind Method; Eplerenone; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertrophy, Left Ventricular; Myocardial Reperfusion; Pyridines; Radiology, Interventional; Spironolactone; Stents; Thiazepines; Thrombolytic Therapy

The vasopeptidase inhibitor omapatrilat improves insulin sensitivity and survival following myocardial infarction (MI). It also improves left ventricular (LV) remodelling following MI and reduces MI size.. To determine whether improvement in LV remodelling and function is accompanied by a reduction in fetal gene expression of the contractile apparatus, and whether reduction in MI size is accompanied by an increase in the expression of the glucose transporter GLUT-4.. Eighty-nine rats were pretreated for seven days with omapatrilat 20 mg/kg/day and 91 rats were left untreated. MI was induced in 180 Zucker lean male rats by ligating the left anterior descending coronary artery, and omapatrilat was given for another 38 days in the survivors. After 30 days, echocardiography was performed. At 38 days, hemodynamic measurements were performed, the rats were sacrificed and morphological measurements were done. Using quantitative reverse transcriptase-polymerase chain reaction, gene expression was measured in the LV using transcript levels.. Treatment with omapatrilat resulted in improved early (24 h) and late (38 days) survival following MI (50% to 67%, P=0.023, and 44% to 59%, P=0.045, respectively). Omapatrilat treatment reduced MI size and resulted in beneficial ventricular remodelling as reflected by a reduction in cardiac dimensions by echocardiography, and LV and right ventricular hypertrophy, which resulted in borderline hemodynamic improvement. A large MI resulted in an increased expression of beta-myosin heavy chain, alpha-skeletal actin and atrial natriuretic peptide, and a decreased expression of GLUT-4. Omapatrilat treatment did not modify the expression of these genes.. The results suggest that the vasopeptidase inhibitor omapatrilat does not modify fetal gene expression of the contractile apparatus or the expression of GLUT-4 despite reducing cardiac hypertrophy and MI size.

Topics: Animals; Atrial Natriuretic Factor; Disease Models, Animal; Drug Evaluation, Preclinical; Echocardiography; Gene Expression Regulation; Glucose Transporter Type 4; Heart Ventricles; Hypertrophy, Left Ventricular; Hypertrophy, Right Ventricular; Ligation; Male; Monosaccharide Transport Proteins; Muscle Proteins; Myocardial Infarction; Protease Inhibitors; Pyridines; Random Allocation; Rats; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; Survival Rate; Thiazepines; Ventricular Function, Left; Ventricular Myosins; Ventricular Remodeling

Congestive heart failure (CHF) results in decreased cardiac sympathetic innervation.. The purpose of this study was to test the hypothesis that therapy with the vasopeptidase inhibitor omapatrilat (OMA) attenuates cardiac neuronal remodeling in CHF.. We induced CHF in dogs with rapid ventricular pacing for 5 weeks with (CHF+OMA group, n = 8) or without (CHF group, n = 10) concomitant OMA treatment (10 mg/kg twice daily). Cardiac catheterization and echocardiography were performed to determine cardiac structure and hemodynamic parameters. Myocardial nerve density was determined by immunocytochemical staining with anti-growth associated protein 43 (GAP43) and anti-tyrosine hydroxylase (TH) antibodies. Seven normal dogs were used as histologic controls.. In the CHF group, ascites developed in 3 dogs and 4 dogs died, compared with no ascites or death in the CHF+OMA group (P = .07). In the 6 CHF dogs that survived, all had atrial fibrosis, severely depressed left ventricular systolic function, and increased atrial and ventricular chamber size. OMA treatment decreased the atrial and ventricular chamber sizes and the degree of atrial fibrosis. Most CHF dogs showed severe myocardial denervation, although some showed normal or abnormally high nerve counts. OMA treatment prevented heterogeneous reduction of nerve density. The left ventricular TH-positive nerve densities were 128 +/- 170 microm(2)/mm(2), 261 +/- 185 microm(2)/mm(2), and 503 +/- 328 microm(2)/mm(2) (P < .05), and the atrial GAP43-positive nerve densities were 1,683 +/- 1,365 microm(2)/mm(2), 305 +/- 368 microm(2)/mm(2), and 1,278 +/- 1,479 microm(2)/mm(2) (P < .05) for the control, CHF, and CHF+OMA groups, respectively.. CHF results in heterogeneous cardiac denervation. Long-term OMA treatment prevented the reduction of nerve density and promoted beneficial cardiac structural remodeling.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cardiovascular Agents; Disease Models, Animal; Dogs; Heart Atria; Heart Failure; Heart Ventricles; Hypertrophy, Left Ventricular; Male; Myocardium; Natriuretic Peptide, Brain; Nerve Tissue; Pyridines; Renin; Stroke Volume; Thiazepines; Ventricular Dysfunction, Left; Ventricular Pressure; Ventricular Remodeling

Topics: Angiotensin-Converting Enzyme Inhibitors; Diabetes Complications; Diabetes Mellitus; Heart Failure; Humans; Hypertrophy, Left Ventricular; Mass Screening; Metalloendopeptidases; Natriuretic Peptide, Brain; Pyridines; Thiazepines; Ventricular Dysfunction, Left

Omapatrilat is a newly developed vasopeptidase inhibitor that inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase and has potent antihypertensive efficacy. However, the specific effect of omapatrilat on cardiac function and left ventricular hypertrophy with hypertension remains controversial. Therefore, we investigated the effect of omapatrilat on blood pressure, cardiac hypertrophy, and cardiac function in spontaneously hypertensive rats (SHR). Studies were performed in SHR that received vehicle (n = 9), omapatrilat (n = 10), or fosinopril (ACE inhibitor, n = 7) by daily gavage for 56 days. Systolic blood pressure (SBP) and mean blood pressure (MBP) were measured by tail plethysmography. Left ventricular fractional shortening and left ventricular mass were measured by echocardiography at day 56. Omapatrilat and fosinopril significantly decreased SBP and MBP from day 1 through day 56, and omapatrilat markedly reduced SBP and MBP compared with fosinopril from day 21 to day 56. Although both omapatrilat and fosinopril decreased left ventricular mass and left ventricular mass-to-body weight ratio with increased LV fractional shortening, omapatrilat had a more potent effect on the reduction of left ventricular mass and improvement of cardiac function. This study shows that in SHR, omapatrilat mediated a potent and stable antihypertensive effect and a reduction in left ventricular mass with improvement of cardiac function, compared with ACE inhibition alone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiovascular Agents; Endocardium; Fosinopril; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Male; Pyridines; Rats; Rats, Inbred SHR; Thiazepines; Ventricular Function, Left

The respective role of angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) in the degradation of bradykinin (BK) has been studied in the infarcted and hypertrophied rat heart. Myocardial infarction (MI) was induced in rats by left descendant coronary artery ligature. Animals were killed, and hearts were sampled 1, 4, and 35 days post-MI. BK metabolism was assessed by incubating synthetic BK with heart membranes from sham hearts and infarcted (scar) and noninfarcted regions of infarcted hearts. The half-life (t1/2) of BK showed significant differences among the three types of tissue at 4 days [sham heart (114 +/- 7 s) > noninfarcted region (85 +/- 4 s) > infarcted region (28 +/- 2 s)] and 35 days post-MI [sham heart (143 +/- 6 s) = noninfarcted region (137 +/- 9 s) > infarcted region (55 +/- 4 s)]. No difference was observed at 1 day post-MI. The participation of ACE and NEP in the metabolism of BK was defined by preincubation of the membrane preparations with enalaprilat, an ACE inhibitor, and omapatrilat, a vasopeptidase inhibitor that acts by combined inhibition of NEP and ACE. Enalaprilat significantly prevented the rapid degradation of BK in every tissue type and at every sampling time. Moreover, omapatrilat significantly increased the t1/2 of BK compared with enalaprilat in every tissue type and at every sampling time. These results demonstrate that experimental MI followed by left ventricular dysfunction significantly modifies the metabolism of exogenous BK by heart membranes. ACE and NEP participate in the degradation of BK since both enalaprilat and omapatrilat have potentiating effects on the t1/2 of BK.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Cell Membrane; Chromatography, High Pressure Liquid; Enalaprilat; Hypertrophy, Left Ventricular; In Vitro Techniques; Male; Myocardial Infarction; Myocardium; Neprilysin; Peptidyl-Dipeptidase A; Pyridines; Rats; Rats, Wistar; Thiazepines; Ventricular Function, Left