Studies showing an association between CRP and post-operative atrial fibrillation (AF) suggest that inflammation plays a role in the pathogenesis of this arrhythmia. ACE inhibitors and AT1 receptor antagonists have been shown to reduce the incidence of AF in patients with myocardial infarction or congestive heart failure. We have demonstrated that ACE inhibition decreases IL-6 and PAI-1 concentrations post-operatively. Based on data from animal studies we hypothesize that this effect occurs in part through ACE inhibitor-induced decreases in aldosterone. In the present study we will test the hypothesis that either ACE inhibition or aldosterone receptor antagonism will decrease the incidence of post-operative AF.

Condition	Intervention	Phase
Atrial Fibrillation	Drug: Spironolactone and Ramipril	Phase II Phase III

Further Study Details: 

Primary Outcomes: a. Test the hypothesis that angiotensin II induces oxidation and inflammation in humans through endogenous aldosterone; b. Test the hypothesis that exogenous aldosterone induces oxidation and inflammation in humans through a mineralocorticoid receptor-dependent mechanism; c. Test the hypothesis that exogenous aldosterone induces oxidation and inflammation in humans through an AT1 receptor-dependent mechanism
Secondary Outcomes: Test the hypothesis that either angiotensin-converting enzyme inhibition or aldosterone receptor antagonism decreases the incidence of atrial fibrillation following cardiopulmonary bypass
Expected Total Enrollment:  1000

Atrial fibrillation Atrial fibrillation (AF) affects more than 2 million Americans and is associated with a twofold increase in total and cardiovascular mortality, related largely to the attendant embolic risk. The annual health care cost of AF has been estimated to be $9 billion. The incidence of AF increases with age, affecting at least 5% of Americans age 65 years and older and 9 percent of those over the age of 80. Thus with the aging of the American population, the prevalence of AF promises to increase dramatically over the next few decades. AF complicates 20% to 40% of surgeries involving cardiopulmonary bypass (CPB). Post-operative AF results in substantial morbidity and prolongation of hospitalization. With 519,000 patients undergoing CPB in the United States each year and an estimated excess cost of $10,000 per patient who develops AF, the annual health care cost of post-operative AF alone reaches $1 billion. Clinical management of AF remains problematic, despite intense efforts in the past decade to develop improved therapy using antiarrhythmic drugs, defibrillators, and ablative procedures. The present proposal focuses on the interruption of the renin-angiotensin-aldosterone system (RAAS) as a novel strategy in the prevention of AF.

Studies in animal models suggest that fibrosis plays a critical role in the pathogenesis of AF.

Mapping studies in animal models and humans have shown that rapid atrial excitation during AF typically results from multiple wavelets of reentrant excitation. Thus, functional or structural abnormalities that promote heterogeneous repolarization within the atria create the substrate for AF, which is usually initiated by a premature atrial contraction. Indeed, clinical AF often results in the setting of conditions associated with inflammation, structural remodeling and fibrosis -- such as hypertension, valvular heart disease, senescence and CPB. Studies in dogs support a role for structural changes in the atria in providing the substrate for AF. For example, Li et al reported that ventricular tachycardia-induced congestive heart failure promotes the induction of AF by causing interstitial fibrosis and interfering with local conduction. Similarly, Shinagawa et al have reported that the induction of atrial fibrosis by ventricular tachypacing renders dogs vulnerable to the induction of AF by an atrial premature extrastimulus. Drug therapy to prevent AF has traditionally targeted atrial electrophysiological mechanisms; however, the proarrhythmic effects of such drug therapy have limited its safety. Data from these dog studies would suggest that an alternative strategy for the prevention of AF would be to prevent inflammation and fibrosis and the development of the AF substrate.

The RAAS and inflammation and fibrosis During inflammation, leukocytes and macrophages migrate into tissues and elaborate cytokines which stimulate local cells to deposit collagens and proteoglycans into the extracellular matrix (ECM). Under normal circumstances this process is kept in check by matrix metalloproteinases and other proteinases that degrade collagen. Fibrosis results when there is an imbalance between the synthesis and degradation of ECM. Previous work in our laboratory has focused on the mechanism(s) through which activation of the RAAS promotes fibrosis.

We, and others, have found that both angiotensin II (Ang II) and aldosterone increase plasminogen activator inhibitor-1 (PAI-1) expression in vitro and in vivo. PAI-1, by inhibiting the production of plasmin from plasminogen, decreases plasmin-induced activation of matrix metalloproteinases, and tips the balance in favor of ECM production and fibrosis.

Increasing evidence indicates that activation of the RAAS exerts proinflammatory effects. For example, Ang II activates the transcription factor nuclear factor (NF)-KB, which in turn regulates genes involved in cellular recruitment and the inflammatory cytokine cascade. Ang II induces the synthesis and secretion of the inflammatory interleukin (IL)-6, while IL-6 increases angiotensinogen synthesis in the liver through a janus kinase (JAK)/signal transducer and activator of transcription (STAT)-3 pathway. In the presence of IL-1, IL-6 also synergistically upregulates C-reactive protein (CRP) and PAI-1. As outlined in more detail below, recent evidence from animal

models also indicates that Ang II causes inflammation and fibrosis, in part, through aldosterone receptor-dependent mechanisms.

The inflammatory effects of aldosterone have not been extensively studied in humans. However, data that indicate that atrial remodeling contributes to the pathogenesis of AF, that activation of the RAAS induces inflammation, myocyte injury, and fibrosis through aldosterone, and that interruption of the RAAS decreases AF in patients following myocardial infarction or cardioversion, suggest the hypothesis that interruption of the RAAS by angiotensin-converting enzyme (ACE) inhibition or aldosterone receptor antagonism will decrease the frequency of post-operative AF following CPB by decreasing inflammation.

AF is associated with inflammation and fibrosis in humans. Several lines of evidence suggest that inflammation and fibrosis may contribute to the pathogenesis of AF in humans. Chung et al reported that circulating CRP concentrations were significantly higher in patients with AF compared with controls, and in patients with persistent AF compared to patients with paroxysmal AF. Similarly, Dernellis and Panaretou have reported that CRP concentrations are increased in patients with paroxysmal AF of recent onset (<24 hours) compared with age- and sex- matched controls, and in patients who failed to convert to sinus rhythm following treatment with amiodarone compared to those who did convert to sinus rhythm. On biopsy, atria from patients with refractory AF exhibit inflammatory infiltrates, myocyte necrosis, and fibrosis. Likewise studies have shown that atria of patients with permanent AF exhibit increased fibrosis, myosin isoform switching, and peroxynitrite-mediated protein nitration.

Inflammation following CPB may contribute to the high rate of post-operative AF.

The incidence of AF following CPB has been reported to be 20% to 40%. In a population of patients undergoing CPB at Vanderbilt, we have observed an incidence of post-operative AF of 16%. Activation of the complement system and the release of pro-inflammatory cytokines during CPB may contribute to the high incidence of post-operative AF. Concentrations of IL-6 peak within 6 hours following CPB. Concentrations of PAI-1 peak 1 to 2 days following bypass, while CRP and complement-CRP complexes peak within 2 to 3 days after bypass. The incidence of atrial arrhythmias also peaks 2 to 3 days after surgery. In non-randomized, retrospective studies, treatment with ACE inhibition has been associated with both a decrease in post-operative IL-6 concentrations and a decrease in the rate of post-operative AF. Significantly, Gaudino et al have reported that a -174G/C polymorphism in the IL-6 gene that influences post-operative IL-6 levels also influences the development of AF. As discussed in PRELIMINARY STUDIES, we have found that randomization to continued ACE inhibition prior to CPB is associated with a decrease in markers of inflammation such as IL-6 and PAI-1.

Interruption of the RAAS by ACE inhibition or AT1 receptor antagonism decreases the incidence of AF following myocardial infarction or cardioversion.

Three large clinical studies indicate that interruption of the RAAS decreases AF. In the Trandolapril Cardiac Evaluation (TRACE) study, patients with left ventricular dysfunction following myocardial infarction were randomized to trandolapril or placebo beginning 3 to 7 days following myocardial infarction. In 1577 patients who were in sinus rhythm at the time of randomization, treatment with trandolapril was associated with a significant decrease in the development of AF (2.8% versus 5.3%, P<0.05) over the 2 to 4 year follow-up period. In the last few months, a retrospective analysis of patients from the Montreal Heart Institute included in the Studies of Left Ventricular Dysfunction trial, indicated that randomization to the ACE inhibitor enalapril reduced the incidence of AF over a 2.9 year follow-up from 24% to 5.4% (P<0.001). In another, prospective clinical trial, Madrid et al reported that, in patients with AF of more than 7 days duration treated with electrical cardioversion followed by amiodarone, randomization to co-treatment with the AT1 receptor antagonist irbesartan decreased the incidence of recurrent AF (63.16% versus 84.79%, P=0.008) at 2 months of follow-up.

Ang II induces inflammation and fibrosis through an aldosterone receptor-dependent mechanism.

The last several years have seen a major paradigm shift in our understanding of how aldosterone contributes to cardiovascular injury. According to classical mechanisms, aldosterone acts primarily as a circulating hormone involved in the regulation of sodium excretion through mineralocorticoid receptor (MR)-dependent

mechanisms. Thus Ang II [or potassium or adrenocorticotropic hormone (ACTH)] stimulates the zona glomerulosa of the adrenal gland to synthesize aldosterone. Circulating aldosterone then binds to the inactive cytosolic MR of

target cells, resulting in dissociation of the ligand-activated MR from a multiprotein complex containing molecular chaperones, translocation of the ligand-activated MR into the nucleus and binding to hormone response elements in the regulatory region of target gene promoters. In the distal nephron of the kidney, the induction of serum and glucocorticoid inducible kinase-1 (sgk-1) gene expression triggers a cascade that leads to the absorption of Na+ ions and water through the epithelial sodium channel and potassium excretion with subsequent volume expansion and hypertension.

Our understanding of the cardiovascular effects of aldosterone has evolved in 3 important areas. First, studies now provide evidence for local, extra-adrenal production of aldosterone, as well as for extra-renal actions of aldosterone. Aldosterone can be synthesized by endothelial cells and vascular smooth muscle cells (VSMC), and locally in tissues such as the brain, blood vessels and, relevant to the present proposal, the myocardium. Synthesis at extra-adrenal sites appears to be regulated by the same stimuli that regulate adrenal synthesis. Moreover, MRs have been identified not only in epithelial cells, but also in the brain, heart, and blood vessels. Taken together these data suggest that aldosterone can exert autocrine or paracrine effects on the heart and blood vessels. Second, studies have provided evidence of rapid non-genomic effects of aldosterone. For example, aldosterone increases Na/H anti-porter activity in VSMC through a membrane, rather than nuclear, receptor. The non-genomic effects of aldosterone are rapid (<5 min), are transcription-independent, and are not blocked by classical aldosterone antagonists, including spironolactone or its active metabolite, canrenone.

Third, and most importantly, aldosterone appears to contribute to the inflammatory and fibrotic effects that previously were attributed solely to Ang II. For example, during high salt intake, aldosterone administration causes myocardial fibrosis and ventricular hypertrophy in rats. Concurrent ACE inhibition blocks the development of ventricular hypertrophy but not the myocardial fibrosis, suggesting that the fibrotic effects of aldosterone occur in the absence of Ang II. MR antagonism with either spironolactone or eplerenone prevents aortic and myocardial fibrosis in rat models of primary and secondary hypertension, even in the absence of blood pressure effects. Studies in the rat by both Rocha et al. and Funder and co-workers indicate that mineralocorticoid/salt treatment induces coronary and myocardial inflammation, characterized by monocyte and macrophage infiltration and by increased expression of the inflammatory markers cyclooxygenase-2, osteopontin, macrophage chemoattractant protein-1, and intracellular adhesion molecule-1; these inflammatory changes can be blocked by MR antagonism. MR antagonism prevents the inflammatory changes induced by treatment with Ang II and the nitric oxide synthase inhibitor NG-nitro-l-arginine-methyl ester (L-NAME). Similarly, MR antagonism decreases activator protein-1 (AP-1) expression, NFKB expression and cardiac fibrosis in rats doubly transgenic for the human renin and angiotensinogen genes.

The mechanism(s) through which aldosterone causes cardiac and vascular fibrosis are the subject of ongoing investigations in this laboratory (R01 HL67308). Sodium appears to be prerequisite in animal models of aldosterone-induced cardiac fibrosis. As outlined above, aldosterone exerts direct pro-fibrotic effects. In addition, aldosterone may enhance the effect of Ang II by increasing AT1 receptor binding in cardiovascular tissue. For example, aldosterone increases AT1 receptor binding in rat VSMCs in a time- and concentration-dependent manner. In the rat heart, aldosterone increases, whereas spironolactone decreases, AT1 receptor density and mRNA accumulation.Regardless of the mechanism, clinical trials have now confirmed the relevance of aldosterone-induced fibrosis in patients with left ventricular dysfunction.

Aldosterone receptor antagonism reduces collagen turnover in humans. Data from the Randomized Aldactone Evaluation Study (RALES) suggest that the favorable effect of aldosterone antagonism on collagen turnover and extracellular matrix formation is not limited to animal models. RALES examined the effect of spironolactone versus placebo on mortality in patients with New York Heart Association (NYHA) class 3 or 4 heart failure who were already treated with an ACE inhibitor, diuretics and digoxin. Significantly, the Data Safety and Monitoring Committee of the study recommended early termination of the trial after 2 years because a statistically significant survival advantage of spironolactone had emerged, with a 27% decrease in all-cause mortality compared to placebo treatment. A similar beneficial effect of aldosterone receptor antagonism was observed in patients with anterior MI and left ventricular dysfunction in the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS).

In a sub-study of RALES, Zannad et al examined the relationship between serological markers of collagen turnover and mortality. They found that elevated concentrations of procollagen type III amino-terminal peptide (PIIINP), a biochemical marker of myocardial fibrosis, were associated with an increased risk of death (relative risk of death 2.36, 95% CI 1.34 to 4.18). Spironolactone significantly decreased procollagen type I amino-terminal peptide (PINP), procollagen type I carboxy-terminal peptide (PICP) and PIIINP. Moreover, the effect of

spironolactone on mortality was significant only in patients whose baseline markers of collagen turnover were above the median concentration. These data have been confirmed in a group of patients with acute anterior myocardial infarction randomized to either spironolactone or placebo. In this study, patients treated with spironolactone had a significantly greater increase in left ventricular ejection fraction (7.20+0.7% versus 4.26+0.8%, P=0.012) and significantly decreased circulating PIIINP concentrations (0.43+0.01 versus 0.51+0.02 pg/ml, P=0.004) compared to placebo-treated patients; PIIINP concentrations correlated significantly with left ventricular end-diastolic volume index. These studies support the hypothesis that aldosterone receptor antagonism affects extracellular matrix turnover in humans.

Ages Eligible for Study:  18 Years   -   80 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

1. Subjects, 18 to 80 years of age, inclusive, scheduled for elective surgery requiring CPB
2. For female subjects, the following conditions must be met:

postmenopausal for at least 1 year, or status-post surgical sterilization, or if of childbearing potential, utilizing adequate birth control and willing to undergo urine beta-hcg testing prior to drug treatment and on every study day

Exclusion Criteria

1. History of prior AF
2. Ejection fraction less than 30%
3. Emergency surgery
4. History of ACE inhibitor-induced angioedema
5. Hypotension (systolic blood pressure <100 mmHg and evidence of hypoperfusion)
6. Hyperkalemia (baseline potassium >5.0 mEq/L)
7. Impaired renal function (serum creatinine >1.5 mg/dl)
8. Pregnancy
9. Breast-feeding
10. Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult
11. Inability to discontinue current ACE inhibitor therapy, ATRA or potassium-sparing diuretic therapy
12. History of alcohol or drug abuse
13. Treatment with any investigational drug in the 1 month preceding the study
14. Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study
15. Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Please refer to this study by ClinicalTrials.gov identifier  NCT00141778

Holly Waldrop      (615)343-6161    holly.waldrop@vanderbilt.edu

Tennessee
      Vanderbilt University, Nashville,  Tennessee,  37232,  United States; Recruiting

Study chairs or principal investigators

Nancy J. Brown, M.D.,  Principal Investigator,  Vanderbilt University   

Study ID Numbers:  040385; HL077389
Last Updated:  August 31, 2005
Record first received:  August 30, 2005
ClinicalTrials.gov Identifier:  NCT00141778
Health Authority: United States: Institutional Review Board
ClinicalTrials.gov processed this record on 2005-09-06