aliskiren and Myocardial-Infarction

Renin inhibitors (RIs) reduce blood pressure more than placebo, with the magnitude of this effect thought to be similar to that for angiotensin converting enzyme (ACE) inhibitors. However, a drug's efficacy in lowering blood pressure cannot be considered as a definitive indicator of its effectiveness in reducing mortality and morbidity. The effectiveness and safety of RIs compared to ACE inhibitors in treating hypertension is unknown.. To evaluate the benefits and harms of renin inhibitors compared to ACE inhibitors in people with primary hypertension.. The Cochrane Hypertension Group Information Specialist searched the following databases for randomized controlled trials up to August 2020: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers about further published and unpublished work. The searches had no language restrictions.. We included randomized, active-controlled, double-blinded studies (RCTs) with at least four weeks follow-up in people with primary hypertension, which compared renin inhibitors with ACE inhibitors and reported morbidity, mortality, adverse events or blood pressure outcomes. We excluded people with proven secondary hypertension.. Two review authors independently selected the included trials, evaluated the risks of bias and entered the data for analysis.. We include 11 RCTs involving 13,627 participants, with a mean baseline age from 51.5 to 74.2 years. Follow-up duration ranged from four weeks to 36.6 months. There was no difference between RIs and ACE inhibitors for the outcomes: all-cause mortality: risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.18; 5 RCTs, 5962 participants; low-certainty evidence; total myocardial infarction: RR 0.86, 95% CI 0.22 to 3.39; 2 RCTs, 957 participants; very low-certainty evidence; adverse events: RR 0.98, 95% CI 0.93 to 1.03; 10 RTCs, 6007 participants;  moderate-certainty evidence; serious adverse events: RR 1.21, 95% CI 0.89 to 1.64; 10 RTCs, 6007 participants; low-certainty evidence; and withdrawal due to adverse effects: RR 0.85, 95% CI 0.68 to 1.06; 10 RTCs, 6008 participants; low-certainty evidence. No data were available for total cardiovascular events, heart failure, stroke, end-stage renal disease or change in heart rate. Low-certainty evidence suggested that RIs reduced systolic blood pressure: mean difference (MD) -1.72, 95% CI -2.47 to -0.97; 9 RCTs, 5001 participants;  and diastolic blood pressure: MD -1.18, 95% CI -1.65 to -0.72; 9 RCTs, 5001 participants,  to a greater extent than ACE inhibitors, but we judged this to be more likely due to bias than a true effect.  AUTHORS' CONCLUSIONS: For the treatment of hypertension, we have low certainty that renin inhibitors (RI) and angiotensin converting enzyme (ACE) inhibitors do not differ for all-cause mortality and myocardial infarction. We have low to moderate certainty that they do not differ for adverse events. Small reductions in blood pressure with renin inhibitors compared to ACE inhibitors are of low certainty.  More independent, large, long-term trials are needed to compare RIs with ACE inhibitors, particularly assessing morbidity and mortality outcomes, but also on blood pressure-lowering effect.

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Cause of Death; Female; Fumarates; Heart Rate; Humans; Irbesartan; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Myocardial Infarction; Patient Dropouts; Ramipril; Randomized Controlled Trials as Topic; Renin

The safety of angiotensin II receptor blockers (ARBs) for the treatment of hypertension and cardiovascular and renal diseases has been well documented in numerous randomized clinical trials involving thousands of patients. However, recent concerns have surfaced about possible links between ARBs and increased risks of myocardial infarction and cancer. Less is known about the safety of the direct renin inhibitor aliskiren, which was approved as an antihypertensive in 2007. This article provides a detailed review of the safety of ARBs and aliskiren, with an emphasis on the risks of cancer and myocardial infarction associated with ARBs. Safety data were identified by searching PubMed and Food and Drug Administration (FDA) Web sites through April 2011. ARBs are generally well tolerated, with no known class-specific adverse events. The possibility of an increased risk of myocardial infarction associated with ARBs was suggested predominantly because the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial reported a statistically significant increase in the incidence of myocardial infarction with valsartan compared with amlodipine. However, no large-scale, randomized clinical trials published after the VALUE study have shown a statistically significant increase in the incidence of myocardial infarction associated with ARBs compared with placebo or non-ARBs. Meta-analyses examining the risk of cancer associated with ARBs have produced conflicting results, most likely due to the inherent limitations of analyzing heterogeneous data and a lack of published cancer data. An ongoing safety investigation by the FDA has not concluded that ARBs increase the risk of cancer. Pooled safety results from clinical trials indicate that aliskiren is well tolerated, with a safety profile similar to that of placebo. ARBs and aliskiren are well tolerated in patients with hypertension and certain cardiovascular and renal conditions; their benefits outweigh possible safety concerns.

Topics: Amides; Angiotensin Receptor Antagonists; Antihypertensive Agents; Fumarates; Humans; Hypertension; Myocardial Infarction; Neoplasms

Aliskiren previously was found to have potentially harmful effects in diabetic individuals prescribed concomitant angiotensin converting enzyme inhibitors (ACEI) or angiotenisn receptor antagonists (ARB). We explored potential effects of aliskiren on coronary atheroma progression and major adverse cardiovascular events (MACE: death/non-fatal MI/non-fatal stroke/hospitalization for heart failure/hospitalization for ACS/arterial revascularization) in patients with and without diabetes mellitus (DM).. AQUARIUS employed serial intravascular ultrasound measures of coronary atheroma volume in coronary artery disease patients randomized to receive daily aliskiren 300 mg or placebo for 104 weeks. This post hoc analysis compared changes in plaque volume [percent atheroma volume (PAV) and total atheroma volume (TAV)] and MACE in patients with (n = 115) and without (n = 343) DM stratified by treatment allocation.. In multivariable propensity-weighted analyses, which included controlling for baseline and concomitant ACEI/ARB therapy and duration of aliskiren therapy, aliskiren-treated non-DM patients demonstrated the greatest PAV and TAV regression, whereas aliskiren-treated DM patients demonstrated the greatest TAV progression and greater PAV. Aliskiren-treated non-DM patients appeared at significantly lower risk of MACE compared with their aliskiren-treated DM counterparts [HR 95% CI 0.28 (0.10, 0.80)]. Statistical interactions were noted between DM status and treatment allocation for both changes in PAV (p < 0.001), TAV (p = 0.010) and MACE (p = 0.057).. Aliskiren appears to be relatively anti-atherosclerotic in non-diabetic patients. Due to the limited number MACE and low numbers of diabetic patients in AQUARIUS, the pro-atherosclerotic effects of aliskiren in this population are inconclusive, and these results should be thus considered hypothesis generating. Further outcome studies are required in non-diabetic patients to confirm the possible favorable effects of aliskiren.

Topics: Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Chi-Square Distribution; Coronary Artery Disease; Coronary Vessels; Diabetic Angiopathies; Disease Progression; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fumarates; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Plaque, Atherosclerotic; Prehypertension; Propensity Score; Proportional Hazards Models; Risk Assessment; Risk Factors; Stroke; Time Factors; Treatment Outcome; Ultrasonography, Interventional

Some patients with acute myocardial infarction (AMI) have a poor prognosis due to left ventricular remodeling (LVR), resulting in the recurrence of congestive heart failure even when therapy with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) has been initiated. We investigated the effect of early administration of the direct renin inhibitor (DRI) aliskiren in combination with an ACEI or an ARB on LVR using cardiac magnetic resonance (CMR) imaging in patients with AMI.Twenty-one consecutive patients were treated with an ACEI or an ARB (non-DRI group), and another 21 consecutive patients received aliskiren 150 mg/day combined with an ACEI or an ARB (DRI group). CMR imaging was performed 7 days after AMI and 10 months later.CMR imaging revealed no significant changes in LV end-systolic volume, LV end-diastolic volume, or LV ejection fraction between the patients with and without DRI aliskiren. In the DRI group, plasma renin activity was significantly lower in both the acute and chronic phases; however, aldosterone levels were significantly lower in the acute but not the chronic phase.A low dose of aliskiren may be insufficient to maintain suppression of aldosterone under current standard therapies with an ACEI or an ARB and β-blocker in patients with primary AMI, and results in no attenuation of LVR.

Topics: Aged; Aldosterone; Amides; Angiotensin II Type 2 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Female; Fumarates; Humans; Male; Middle Aged; Myocardial Infarction; Renin; Ventricular Remodeling

We assessed the relationship between diabetes and cardiac structure and function following myocardial infarction (MI) and whether diabetes influences the effect of direct renin inhibition on change in left ventricular (LV) size.. The ASPIRE trial enrolled 820 patients 2-8 weeks after MI with ejection fraction ≤ 45% and randomized them to the direct renin inhibitor aliskiren (n= 423) or placebo (n = 397) added to standard medical therapy. Echocardiography was performed at baseline and after 36 weeks in 672 patients with evaluable paired studies. Compared with non-diabetic patients, diabetic patients (n = 214) were at higher risk for a composite of cardiovascular (CV) death, heart failure hospitalization, recurrent MI, stroke, or aborted sudden death (14 vs. 7%; adjusted hazard ratio 1.63, 95% confidence interval 1.01-2.64, P= 0.045), despite similar left ventricular ejection fraction (37.9 ± 5.3 vs. 37.6 ± 5.2%, P= 0.48) and end-systolic volume (ESV) (84 ± 25 vs. 82 ± 28 mL, P= 0.46). Diabetic patients demonstrated greater concentric remodelling (relative wall thickness 0.38 ± 0.07 vs. 0.36 ± 0.07, P= 0.0002) and evidence of higher LV filling pressure (E/E' 11.1 ± 5.3 vs. 9.1 ± 4.3, P= 0.0011). At 36 weeks, diabetic patients experienced similar per cent reduction in ESV overall (-4.9 ± 17.9 vs. -5.5 ± 16.9, P= 0.67) but tended to experience greater reduction in ESV than non-diabetic patients when treated with aliskiren (interaction P = 0.08).. Compared with non-diabetic patients, diabetic patients are at increased risk of CV events post-MI despite no greater LV enlargement or reduction in systolic function. Diabetic patients demonstrate greater concentric remodelling and evidence of higher LV filling pressure, suggesting diastolic dysfunction as a potential mechanism for the higher risk observed among these patients.

Topics: Aged; Amides; Cardiovascular Agents; Diabetic Cardiomyopathies; Diastole; Double-Blind Method; Female; Fumarates; Humans; Male; Middle Aged; Myocardial Infarction; Renin; Systole; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Direct renin inhibitors provide an alternative approach to inhibiting the renin-angiotensin-aldosterone system (RAAS) at the most proximal, specific, and rate-limiting step. We tested the hypothesis that direct renin inhibition would attenuate left ventricular remodelling in patients following acute myocardial infarction receiving stable, individually optimized therapy, including another inhibitor of the RAAS.. We randomly assigned 820 patients between ∼2 and 8 weeks following acute myocardial infarction, with the left ventricular ejection fraction (LVEF) ≤45%, and regional wall motion abnormalities (≥20% akinetic area), to receive aliskiren (n = 423), titrated to 300 mg, or matched placebo (n = 397), added to the standard therapy. All patients were required to be on a stable dose of an ACE-inhibitor or ARB, and beta-blocker unless contraindicated or not tolerated. Echocardiograms were obtained at baseline, and following 26-36 weeks of treatment. The primary endpoint was change in left ventricular end-systolic volume from baseline to 36 weeks, and was evaluable in 329 patients in the placebo group and 343 patients in the aliskiren group. We observed no difference in the primary endpoint of end-systolic volume change between patients randomized to aliskiren (-4.4 ± 16.8 mL) or placebo (-3.5 ± 16.3 mL), or in secondary measures of end-diastolic volume, or LVEF. We also observed no differences in a composite endpoint of cardiovascular death, hospitalization for heart failure, or reduction in LVEF >6 points. There were more investigator reported adverse events in the aliskiren group, including hypotension, increases in creatinine and hyperkalaemia.. Adding the direct renin inhibitor aliskiren to the standard therapy, including an inhibitor of the RAAS, in high-risk post-MI patients did not result in further attenuation of left ventricular remodelling, and was associated with more adverse effects. These findings do not suggest that dual RAAS blockade with aliskiren would provide additional benefit in these high-risk post-MI patients.

Topics: Aged; Amides; Blood Pressure; Cardiotonic Agents; Death, Sudden, Cardiac; Female; Fumarates; Hospitalization; Humans; Male; Middle Aged; Myocardial Infarction; Recurrence; Renin; Systole; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

Elevated natriuretic peptides (NPs) are associated with an increased cardiovascular risk following acute coronary syndromes (ACSs). However, the therapeutic implications are still undefined. We hypothesized that early inhibition of renin-angiotensin-aldosterone system (RAAS) in patients with preserved left ventricular function but elevated NPs but following ACS would reduce haemodynamic stress as reflected by a greater reduction NP compared with placebo.. AVANT GARDE-TIMI 43 trial, a multinational, double-blind trial, randomized 1101 patients stabilized after ACS without clinical evidence of heart failure or left ventricular function

Topics: Acute Coronary Syndrome; Aged; Amides; Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Death, Sudden, Cardiac; Double-Blind Method; Female; Fumarates; Hospitalization; Humans; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Renin; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

Cardioprotective potential of aliskiren against isoproterenol-induced myocardial infarction was evaluated in this study.. Isoproterenol treatment caused a significant increase in cardiac markers, malondialdehyde, and caspase-3 levels with a considerable decrease in reduced glutathione, superoxide dismutase and catalase enzyme levels. Aliskiren at 50 and 100 mg/kg doses significantly alleviated the increase of caspase-3 and cardiac marker enzymes as well as the changes in antioxidant enzymes, which was confirmed by histopathological analysis. Aliskiren (100 mg/kg) produced more pronounced protective effects than its other two doses. Moreover, the changes in per se group were insignificant as compared to normal control group.. The present study thus provides an evidence for the protective effects of aliskiren in isoproterenol-induced myocardial infarction.

Topics: Amides; Animals; Biomarkers; Cardiotonic Agents; Catalase; Creatine Kinase, MB Form; Dose-Response Relationship, Drug; Fumarates; Glutathione; Isoproterenol; Male; Malondialdehyde; Myocardial Infarction; Myocardium; Rats; Renin; Superoxide Dismutase

This study examined the effects of aliskiren (Ali) (direct renin inhibitor) on serum cardiac enzymes (LDH and CK-MB), electrocardiography (ECG) changes, myocardial oxidative stress markers (MDA, CAT, and GSH) and the expression of Bcl2, HO-1, and Nrf2 genes in isoproterenol (ISO)-induced myocardial infarction (MI). A total of 40 male albino rats were allocated into four groups, (1) normal control (NC) group, (2) Ali group (rats received Ali at 10 mg/kg/day p.o. for 5 days), (3) ISO group (rats received ISO 150 mg/kg i.p. for two consecutive days at 24 h intervals), and (4) Ali + ISO group (rats received ISO + Ali at 10 mg/kg/day p.o. for 5 days from the 2

Topics: Amides; Animals; Apoptosis; Cardiotonic Agents; Fumarates; Isoproterenol; Male; Myocardial Infarction; Oxidative Stress; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress.

Topics: Amides; Animals; Fumarates; Heart; Heart Failure; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Myocardial Infarction; Oxidative Stress; Prorenin Receptor; Protease Inhibitors; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Signal Transduction

Angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor blockers reduce myocardial ischemia-reperfusion injury via bradykinin B2 receptor- and angiotensin AT2 receptor-mediated mechanisms. The renin inhibitor aliskiren increases cardiac tissue kallikrein and bradykinin levels. In the present study, we investigated the effect of aliskiren on myocardial ischemia-reperfusion injury and the roles of B2 and AT2 receptors in this effect. Female Sprague-Dawley rats were treated with aliskiren (10 mg/kg per day) and valsartan (30 mg/kg per day), alone or in combination, together with the B2 receptor antagonist icatibant (0.5 mg/kg per day) or the AT2 receptor antagonist PD123319 (30 mg/kg per day), for 4 weeks before myocardial ischemia-reperfusion injury. Aliskiren increased cardiac bradykinin levels and attenuated valsartan-induced increases in plasma angiotensin II levels. In vehicle-treated rats, myocardial infarct size (% area at risk, mean±SEM, n=7-13) was 43±3%. This was reduced to a similar extent by aliskiren, valsartan, and their combination to 24±3%, 25±3%, and 22±2%, respectively. Icatibant reversed the cardioprotective effects of aliskiren and the combination of aliskiren plus valsartan, but not valsartan alone, indicating that valsartan-induced cardioprotection was not mediated by the B2 receptor. PD123319 reversed the cardioprotective effects of aliskiren, valsartan, and the combination of aliskiren plus valsartan. Aliskiren protects the heart from myocardial ischemia-reperfusion injury via a B2 receptor- and AT2 receptor-mediated mechanism, whereas cardioprotection by valsartan is mediated via the AT2 receptor. In addition, aliskiren attenuates valsartan-induced increases in angiotensin II levels, thus preventing AT2 receptor-mediated cardioprotection by valsartan.

Topics: Amides; Angiotensin II Type 2 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Bradykinin; Bradykinin B2 Receptor Antagonists; Cardiotonic Agents; Drug Therapy, Combination; Female; Fumarates; Imidazoles; Models, Animal; Myocardial Infarction; Myocardial Reperfusion Injury; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2; Receptor, Bradykinin B2; Tetrazoles; Valine; Valsartan

We tested the hypothesis that direct renin inhibition with aliskiren protects against myocardial ischemia/reperfusion (I/R) injury in spontaneously hypertensive rats (SHR), and examined the mechanism by which this occurs.. Male SHR were treated (orally, 4 weeks) with saline or aliskiren (30 or 60 mg kg(-1) day(-1)) and subjected to 30 minutes of left anterior descending coronary artery occlusion followed by 6 or 24 hours of reperfusion. Only the higher dose significantly lowered systolic blood pressure, the lower dose causing a smaller apparent lowering that was nonsignificant. Despite this difference in blood pressure-lowering effect, both doses increased the ejection fraction and fractional shortening and reduced myocardial infarct size equally. I/R decreased cardiac expression of phosphatidylinositol 3-kinase (PI3K), phospho-Akt and phospho-endothelial nitric oxide synthase (phospho-eNOS), but increased expression of inducible nitric oxide synthase (iNOS); these changes were all abrogated by aliskiren. Moreover, aliskiren decreased superoxide anion generation and increased cyclic guanosine-3',5'-monophosphate, an index of bioactive nitric oxide, in myocardium. It also decreased the expression of myocardial matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 (TIMP-1) following I/R. In a Langendorff heart preparation, the detrimental cardiac effects of I/R were abrogated by aliskiren, and these protective effects were abolished by NOS or PI3K inhibition. In a parallel study, although specific iNOS inhibition reduced plasma malondialdehyde and myocardial superoxide anion generation, it did not affect the deleterious effects of I/R on myocardial structure and function.. Direct renin inhibition protects against myocardial I/R injury through activation of the PI3K-Akt-eNOS pathway.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Fumarates; Hypertension; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Renin; Signal Transduction; Stroke Volume; Superoxides; Tissue Inhibitor of Metalloproteinase-1; Ventricular Function, Left

We evaluated whether aliskiren, valsartan, or a combination of both was protective following myocardial infarction (MI) through effects on matrix metalloproteinase (MMP)-9. C57BL/6J wild type (WT, n=94) and MMP-9 null (null, n=85) mice were divided into 4 groups at 3h post-MI: saline (S), aliskiren (A; 50mg/kg/day), valsartan (V; 40mg/kg/day), or A+V and compared to no MI controls at 28days post-MI. All groups had similar infarct areas, and survival rates were higher in the null mice. The treatments influenced systolic function and hypertrophy index, as well as extracellular matrix (ECM) and inflammatory genes in the remote region, indicating that primary effects were on the viable myocardium. Saline treated WT mice showed increased end systolic and diastolic volumes and hypertrophy index, along with reduced ejection fraction. MMP-9 deletion improved LV function post-MI. Aliskiren attenuated the increase in end systolic volume and hypertrophy index, while valsartan improved end diastolic volumes and aliskiren+valsartan improved the hypertrophy index only when MMP-9 was absent. Extracellular matrix and inflammatory gene expression showed distinct patterns among the treatment groups, indicating a divergence in mechanisms of remodeling. This study shows that MMP-9 regulates aliskiren and valsartan effects in mice. These results in mice provide mechanistic insight to help translate these findings to post-MI patients.

Topics: Amides; Animals; Antihypertensive Agents; Drug Therapy, Combination; Extracellular Matrix; Female; Fumarates; Gene Expression; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardium; Stroke Volume; Survival Analysis; Systole; Tetrazoles; Valine; Valsartan; Ventricular Function, Left; Ventricular Remodeling

Aliskiren is an oral renin inhibitor, which inhibits the first rate limiting step in the renin angiotensin aldosterone system. In this study, sympathetic nerve sprouting and the inducibility of ventricular fibrillation after aliskiren treatment in myocardial infarction were investigated.. Male Sprague Dawley rats after coronary artery ligation were randomly allocated to four groups: angiotensin converting enzyme inhibitor enalapril, angiotensin receptor blocker valsartan, β adrenergic receptor blocker carvedilol and rennin inhibitor aliskiren treatment for six weeks. Electrophysiological study, histological examination and Western blotting were performed.. The plasma norepinephrine level and sympathetic nerve innervation significantly increased in treated infarcted rats compared to untreated rats. Aliskiren treatment reduced the sympathetic nerve innervations after myocardial infarction. There is no significant difference in sympathetic nerve innervations after myocardial infarction among the enalapril, valsartan, carvediloand or aliskiren treated groups. Programmed electrical stimulation study showed that inducible ventricular arrhythmia was reduced, ventricular fibrillation threshold was increased and ventricular effective refractory period was prolonged in enalapril, valsartan, carvedilol and aliskiren treated infarcted rats compared to untreated infarcted rats. Cardiomyocytic apoptosis in infarcted region was significantly decreased in enalapril, valsartan, carvedilol and aliskiren treated infarcted rats.. Aliskiren ameliorated cardiomyocytic apoptosis, attenuated the sympathetic nerve innervations and reduced the vulnerability of ventricular arrhythmias after myocardial infarction. Enalapril, valsartan and carvedilol have similar effects as aliskiren on cardiomyocytic apoptosis, sympathetic nerve innervations and vulnerability of ventricular arrhythmias after myocardial infarction.

Topics: Amides; Animals; Fumarates; Male; Myocardial Infarction; Norepinephrine; Rats; Rats, Sprague-Dawley; Renin; Sympathetic Nervous System; Tachycardia, Ventricular

Diminishing the activity of the renin-angiotensin system (RAS) plays a pivotal role in the treatment of heart failure. In addition to angiotensin converting enzyme (ACE) inhibitors and angiotensin-receptor blockers, direct renin inhibition has emerged as a potential adjunctive treatment to conventional RAS blockade. We sought to determine the effectiveness of this strategy after myocardial infarction (MI) in the setting of preexisting hypertension, a common premorbid condition in patients with ischemic heart disease.. Ten-week-old female heterozygous hypertensive (mRen-2)27 transgenic rats (Ren-2), were randomized to one of five groups (n = 8 per group); sham, MI, MI + aliskiren, MI + lisinopril and MI + combination lisinopril and aliskiren. Cardiac function was assessed by echocardiography and in vivo cardiac catheterization. Untreated MI animals developed heart failure with hypotension, dilation, reduced ejection fraction (EF), and raised left ventricular end-diastolic pressure (LVEDP). Treatment with single agent treatment had only modest effect on cardiac function though combination therapy was associated with significant improvements in EF and LVEDP when compared to untreated MI animals (P < 0.05). Histologic analysis demonstrated increase extracellular matrix deposition and cardiomyocyte hypertrophy in the noninfarct region of all MI groups when compared with sham operated animals (P < 0.05) that was reduced by ACE inhibitor monotherapy and combination treatment but not by aliskiren alone.. In a hypertensive rat model that underwent experimental MI, EF, and LVEDP, key functional indices of heart failure, were improved by treatment with combination ACE and direct renin inhibition when compared with either agent used alone.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Catheterization; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Female; Fumarates; Heart Failure; Hypertension; Lisinopril; Myocardial Infarction; Myocardium; Random Allocation; Rats; Rats, Transgenic; Recovery of Function; Renin; Renin-Angiotensin System; Stroke Volume; Ventricular Function, Left; Ventricular Pressure; Ventricular Remodeling

The efficacy of aliskiren, a direct renin inhibitor, in ventricular remodeling after myocardial infarction (MI) compared with conventional renin-angiotensin system (RAS) inhibitors remains to be defined. This study was performed to examine the protective effects of aliskiren and its addition to valsartan, an angiotensin-II receptor blocker, against ventricular remodeling after MI. MI was induced in 8- to 12-week-old C57BL/6 mice by ligating the left anterior descending artery. At 3 days after MI, mice were divided into five groups and were treated with the following: (1) phosphate-buffered saline (PBS); (2) hydralazine (10 mg kg(-1) day(-1)); (3) valsartan (8 mg kg(-1) day(-1)); (4) aliskiren (25 mg kg(-1) day(-1)); and (5) combined aliskiren (25 mg kg(-1) day(-1)) and valsartan (8 mg kg(-1) day(-1)). With these doses of drugs, blood pressure-lowering effects compared with the PBS group were similar among the treated groups in sham-operated mice. At 28 days after MI, echocardiographic, hemodynamic and histological assessments demonstrated that monotherapy with valsartan or aliskiren alone significantly and similarly ameliorated ventricular remodeling after MI compared with the PBS and the hydralazine groups. Combination therapy of valsartan and aliskiren more greatly improved ventricular remodeling after MI with enhancement of angiogenesis and greater attenuation of tissue oxidative stress and inflammation. Our results indicate that aliskiren can be an alternative to conventional RAS inhibitors in the treatment of post-MI patients. Moreover, the dual therapy of valsartan and aliskiren may be more beneficial than either monotherapy. Further clinical trials will be warranted to sufficiently assess the safety and the efficacy of the use of aliskiren in post-MI patients.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Drug Synergism; Fumarates; Heart; Lipid Peroxidation; Male; Mice; Myocardial Infarction; Myocardium; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan; Ventricular Remodeling

Topics: Amides; Animals; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Female; Fumarates; Humans; Male; Myocardial Infarction; Renin; Ventricular Dysfunction, Left; Ventricular Remodeling

It remains unclear whether angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) have fully delivered the expected reduction in cardiovascular diseases. We investigated the effects of adding the direct renin inhibitor (DRI), aliskiren, to an ACEI or an ARB on monocyte subsets and myocardial salvage in patients with primary acute myocardial infarction (AMI).. Twenty-one consecutive patients were treated with an ACEI or an ARB (non-DRI group), and another 21 consecutive patients received aliskiren combined with an ACEI or an ARB (DRI group). Two monocyte subsets (CD14(+)CD16(-) and CD14(+)CD16(+)) were measured by flow cytometry. The extent of myocardial salvage 7 days after AMI was evaluated by cardiac magnetic resonance imaging. Both plasma renin activity and aldosterone levels were significantly lower in the DRI group than in the non-DRI group. Peak levels of CD14(+)CD16(-) monocyte number and ratio were also significantly lower in the DRI group. The extent of myocardial salvage was significantly higher in the DRI group than in the non-DRI group (44.8 [41.2-53.1] vs. 36.0 [28.5-42.6], P=0.001).. A DRI combined with an ACEI or an ARB can better improve the extent of myocardial salvage after AMI than an ACEI or an ARB alone in association with the decrease in circulating CD14(+)CD16(-) monocytes.

Topics: Aged; Aldosterone; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Chi-Square Distribution; Drug Therapy, Combination; Female; Flow Cytometry; Fumarates; GPI-Linked Proteins; Humans; Japan; Lipopolysaccharide Receptors; Magnetic Resonance Imaging; Male; Middle Aged; Monocytes; Myocardial Infarction; Myocardium; Prospective Studies; Receptors, IgG; Renin; Renin-Angiotensin System; Time Factors; Treatment Outcome

In addition to hypertension control, direct renin inhibition has been shown to exert direct beneficial effects on the heart in post-infarction cardiac remodeling. This study elucidates the possible contribution of mitochondria to the anti-hypertrophic effects of the direct renin inhibitor aliskiren in post-infarction heart failure complicated with diabetes in rats.. Diabetes was induced in male Sprague-Dawley rats by a single injection of streptozotocin (IP, 65 mg/kg body weight). After 7 days, the animals were randomly assigned to 4 groups: sham, heart failure, sham+aliskiren, and heart failure+aliskiren. Post-infarction HF was induced by coronary artery ligation for 4 weeks.. showed that heart failure reduced ejection fraction and cardiac output by 41% (P<0.01) and 42% (P<0.05), respectively, compared to sham-operated hearts. Cardiac dysfunction was associated with suppressed state 3 respiration rates and respiratory control index in mitochondria, and increased mitochondrial permeability transition pore (PTP) opening. In addition, heart failure reduced expression of the major mitochondrial sirtuin, SIRT3 and increased acetylation of cyclophilin D, a regulatory component of the PTP. Aliskiren significantly improved cardiac function and abrogated mitochondrial perturbations.. Our results demonstrate that aliskiren attenuates post-infarction remodeling which is associated with its beneficial effects on mitochondria.

Topics: Amides; Animals; Blotting, Western; Diabetes Mellitus, Experimental; Echocardiography; Electrophoresis, Polyacrylamide Gel; Fumarates; Heart Failure; Male; Mitochondria, Heart; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Renin; Reverse Transcriptase Polymerase Chain Reaction

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Female; Fumarates; Humans; Male; Monocytes; Myocardial Infarction; Myocardium; Renin; Renin-Angiotensin System

The complex pathophysiological interactions between heart and kidney diseases are collectively known as cardiorenal syndrome. The renin-angiotensin system (RAS) may have a pivotal role in the development of cardiorenal syndrome. The aim of this study was to elucidate the RAS activity responsible for adverse post-infarction remodeling and prognosis in mice with renal failure. To establish the type IV cardiorenal syndrome model, 5/6 nephrectomy (NTX) was performed in a surgical procedure, followed by the induction of myocardial ischemia (MI) by a coronary artery ligation 4 weeks later. NTX and MI resulted in deteriorated left ventricular remodeling and RAS activation, which was improved by an aliskiren that appeared to be independent of renal function and blood pressure (BP). Moreover, MI induced in renin and angiotensinogen double-transgenic (Tg) mice showed comparable effects to MI plus NTX mice, including advanced ventricular remodeling and enhancement of RAS, oxidative stress, and monocytes chemoattractant protein (MCP)-1. Aliskiren suppressed these changes in the MI-induced Tg mice. In in vitro study, Nox2 expression was elevated by the stimulation of plasma from NTX mice in isolated neonatal cardiomyocytes. However, Nox2 upregulation was negated when we administered plasma from aliskiren-treated-NTX mice or isolated cardiomyocytes from AT1-deficient mice. Primary mononuclear cells also showed an upregulation in the expression of Nox2 and MCP-1 by stimulation with plasma from NTX mice. Our data suggest that renal disorder results in ventricular dysfunction and deteriorates remodeling after MI through excessive RAS activation. Moreover, renin inhibition improved the changes caused by cardiorenal syndrome.

Topics: Amides; Analysis of Variance; Animals; Atrial Natriuretic Factor; Chemokine CCL2; Disease Models, Animal; Fumarates; Humans; Hypertension; Kaplan-Meier Estimate; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction; Myocardium; Nephrectomy; Oxidative Stress; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Ventricular Remodeling

Topics: Adrenergic beta-Antagonists; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Drug Therapy, Combination; Fumarates; Humans; Molecular Targeted Therapy; Myocardial Infarction; Myocardium; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Treatment Outcome; Ventricular Remodeling

Increasing evidence suggests that local renin-angiotensin system (RAS) plays an important role in cardiac diseases. Elevated p90 ribosomal S6 kinase (RSK) activity has been observed in diabetic animal, as well as in human failing hearts. We hypothesize that RSK mediates cardiac dysfunction by up regulating local RAS signaling. In the present study, we show that the prorenin mRNA level was significantly increased (~5.6-fold) in transgenic mouse hearts with cardiac specific expression of RSK (RSK-Tg). The RSK-Tg mice were more vulnerable to ischemia/reperfusion (I/R) injury than non-transgenic littermate controls (NLC). To further understand the direct contribution of cardiac renin to I/R injury, we used a Langendorff system to evaluate the effect of renin inhibition by aliskiren in RSK-Tg mouse hearts. In the vehicle-perfused group, I/R significantly decreased left ventricular developed pressure (LVDP) in RSK-Tg hearts compared to NLC (7% versus 60% of the baseline). However, aliskiren perfusion significantly increased LVDP in RSK-Tg (7% to 61%, p<0.01) but not in NLC hearts (60% to 62%, n.s.). The protective effect of aliskiren in RSK-Tg hearts was further demonstrated with positive (contraction) dp/dt (6.5% to 63%, p<0.01) and rate pressure product (RPP) (5% to 51%, p<0.01). Moreover, aliskiren significantly decreased I/R induced infarction in RSK-Tg (60% to 32%, p<0.01), compared to NLC hearts (37% to 32%, n.s.). These results suggest that RSK plays a crucial role in regulating local cardiac renin, which contributes to I/R induced cardiac injury and dysfunction. Thus, renin inhibition may provide an alternative therapeutic strategy under conditions of increased RAS.

Topics: Amides; Animals; Fumarates; Gene Expression Regulation; Heart; Mice; Mice, Transgenic; Myocardial Infarction; Myocardium; Renin; Renin-Angiotensin System; Reperfusion Injury; Ribosomal Protein S6 Kinases; RNA, Messenger

We assessed the ability of Aliskiren (AL), a direct renin inhibitor, and Valsartan (VA), an angiotensin receptor blocker, to limit myocardial infarct size (IS) in mice with type-2 diabetes mellitus.. Db/Db mice, fed Western Diet, received 15-day pretreatment with: 1) vehicle; 2) AL 25 mg/kg/d; 3) AL 50 mg/kg/d; 4) VA 8 mg/kg/d; 5) VA 16 mg/kg/d; 6) AL 25+VA 16 mg/kg/d; or 7) AL 50+VA 16 mg/kg/d. Mice underwent 30 min coronary artery occlusion and 24 h reperfusion. Area at risk (AR) was assessed by blue dye and IS by TTC staining. Protein expression was assessed by immunobloting.. IS in the control group was 42.9 ± 2.1% of the AR. AL at 25 (21.9 ± 2.9%) and 50 mg/kg/d (15.5 ± 1.3%) reduced IS. VA at 16 mg/kg/d (18.8 ± 1.2%), but not at 8 mg/kg/d (35.2 ± 4.0%), limited IS. IS was the smallest in the AL50+VA16 group (6.3 ± 0.9%). Both AL and VA reduced myocardial AT1R levels, without affecting AT2R levels, and increased the expression of Sirt1 and PGC-1α with increased phosphorylation of Akt and eNOS.. AL, dose dependently limited myocardial IS in mice with type-2 diabetes mellitus. At doses shown to limit IS in non-diabetic animals, VA failed to reduce IS in Db/Db mice. However, at higher dose (16 mg/kg/d), VA reduced IS. Both drugs reduced the expression of AT1R and increased myocardial levels of the longevity genes Sirt1 and PGC-1α along with increased Akt and eNOS phosphorylation.

Topics: Administration, Oral; Amides; Angiotensin II Type 1 Receptor Blockers; Animals; Diabetes Mellitus, Experimental; Drug Therapy, Combination; Fumarates; Hemodynamics; Immunoblotting; Male; Mice; Mice, Inbred Strains; Myocardial Infarction; Myocardial Reperfusion Injury; Receptor, Angiotensin, Type 1; Renin; Tetrazoles; Valine; Valsartan

Angiotensin I-converting enzyme (ACE; kininase II) levels in humans are genetically determined. ACE levels have been linked to risk of myocardial infarction, but the association has been inconsistent, and the causality underlying it remains undocumented. We tested the hypothesis that genetic variation in ACE levels influences myocardial tolerance to ischemia. We studied ischemia-reperfusion injury in mice bearing 1 (ACE1c), 2 (ACE2c, wild type), or 3 (ACE3c) functional copies of the ACE gene and displaying an ACE level range similar to humans. Infarct size in ACE1c was 29% lower than in ACE2c (P<0.05). Pretreatment with a kinin B2 receptor antagonist suppressed this reduction. In ACE3c, infarct size was the same as in ACE2c. But ischemic preconditioning, which reduced infarct size in ACE2c (-63%, P<0.001) and ACE1c (-52%, P<0.05), was not efficient in ACE3c (-2%, NS, P<0.01 vs. ACE2c). In ACE3c, ischemic preconditioning did not decrease myocardial inflammation or cardiomyocyte apoptosis. Pretreatment with a renin inhibitor had no cardioprotective effect in ACE2c, but in ACE3c partially restored (38%) the cardioprotection of ischemic preconditioning. Thus, a modest genetic increase in ACE impairs myocardial tolerance to ischemia. ACE level plays a critical role in cardiac ischemia, through both kinin and angiotensin mediated mechanisms.

Topics: Amides; Angiotensin I; Angiotensin II; Animals; Apoptosis; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Fumarates; Heart; Kinins; Lung; Mice; Mice, Mutant Strains; Myocardial Infarction; Myocardial Ischemia; Myocardium; Peptidyl-Dipeptidase A; Renin; Reperfusion Injury

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Fumarates; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Myocardial Infarction; Patient Readmission; Renin; Renin-Angiotensin System; Treatment Outcome

Pharmacological renin inhibition with aliskiren is an effective antihypertensive drug treatment, but it is currently unknown whether aliskiren is able to attenuate cardiac failure independent of its blood pressure-lowering effects. We investigated the effect of aliskiren on cardiac remodeling, apoptosis, and left ventricular (LV) function after experimental myocardial infarction (MI). C57J/bl6 mice were subjected to coronary artery ligation and were treated for 10 days with vehicle or aliskiren (50 mg/kg per day via an SC osmopump), whereas sham-operated animals served as controls. This dose of aliskiren, which did not affect systemic blood pressure, improved systolic and diastolic LV function, as measured by the assessment of pressure-volume loops after MI. Furthermore, after MI LV dilatation, cardiac hypertrophy and lung weights were decreased in mice treated with aliskiren compared with placebo-treated mice after MI. This was associated with a normalization of the mitogen-activated protein kinase P38 and extracellular signal-regulated kinases 1/2, AKT, and the apoptotic markers bax and bcl-2 (all measured by Western blots), as well as the number of TUNEL-positive cells in histology. LV dilatation, as well as the associated upregulation of gene expression (mRNA abundance) and activity (by zymography) of the cardiac metalloproteinase 9 in the placebo group after MI, was also attenuated in the aliskiren-treated group. Aliskiren improved LV dysfunction after MI in a dose that did not affect blood pressure. This was associated with the amelioration of cardiac remodelling, hypertrophy, and apoptosis.

Topics: Amides; Animals; Antihypertensive Agents; Apoptosis; Blood Pressure; Cardiomegaly; Collagen; Extracellular Matrix; Fumarates; Hypertension, Renal; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Renin; RNA, Messenger; Tissue Inhibitor of Metalloproteinase-1; Ventricular Function, Left; Ventricular Remodeling

The Clinical Trials described in this article were presented at the Hotline and Clinical Trial Update Sessions of the European Society of Cardiology Congress held in September 2007 in Vienna, Austria. The sessions chosen for this article represent the scope of interest of Cardiovascular Drugs and Therapy. The presentations should be considered preliminary, as further analyses could alter the final publication of the results of these studies. PROSPECT evaluated echocardiographic criteria for optimal selection of patients with moderate to severe heart failure who may benefit from cardiac resynchronisation therapy, however concluded that no single echocardiographic measure can be recommended. EVEREST found that tolvaptan, a vasopressin V(2) antagonist, resulted in early weight reduction and improvement of dyspnoea in patients with acute heart failure, but lacked long term improvement. In ARISE, the anti-oxidant succinobucal did not affect the primary outcome in high risk cardiovascular patients, but improved the combination of cardiovascular death, myocardial infarction and stroke, and diabetic control in diabetics. ALOFT showed that the addition of the renin inhibitor aliskiren to an ACE inhibitor or ARB and a beta-blocker leads to favourable effects on neurohormonal actions in heart failure. FINESSE markedly improved coronary patency before PCI with half-dose reteplase/abciximab in STEMI patients, however without significantly improving short-term outcome. The Prague-8 Study evaluated whether routine clopidogrel administered >6 h pre-angiography would be a safe way to achieve therapeutic drug levels in case a follow-up intervention would be considered immediately, but appeared not justified because of bleeding complications. CARESS in MI showed that high risk patients with evolving STEMI who undergo thrombolytic therapy should undergo PCI early after the thrombolysis. Finally, the ACUITY trial found that in moderate or high risk Non ST elevation ACS patients triaged to PCI, coronary artery bypass graft (CABG) surgery, or medical management, bivalirudin, with or without associated GPIIb/IIIa inhibitor therapy, resulted in a marked reduction of bleeding at 30 days whilst preserving the ischemic and mortality benefit at 1 year follow up.

Topics: Abciximab; Acute Coronary Syndrome; Amides; Antibodies, Monoclonal; Benzazepines; Clinical Trials as Topic; Clopidogrel; Electrocardiography; Europe; Fumarates; Heart Diseases; Heart Failure; Hirudins; Humans; Immunoglobulin Fab Fragments; Myocardial Infarction; Peptide Fragments; Probucol; Recombinant Proteins; Ticlopidine; Tolvaptan