Progressive Left Ventricular Remodeling Research Articles

Abstract 2668: Critical Role of Granzyme B in Left Ventricular Remodeling after Acute Myocardial Infarction

Background: Granzyme B is a member of the serine esterase family produced by cytotoxic T lymphocytes (CTLs), and has an important role in cellular apoptosis and extracellular matrix degradation. We hypothesized that granzyme B is involved in left ventricular (LV) remodeling after acute myocardial infarction (AMI). Objectives: To elucidate the role of granzyme B in LV remodeling after AMI. Subjects and methods: We employed 41 patients with the first AMI (mean age: 61.9±8.9 years old). We obtained peripheral blood on day 1, day 7 and day 14 after onset. Plasma levels of apoptosis-related molecules, including tumor necrosis factor α (TNFα), a soluble form of the Fas ligand (sFasL) and granzyme B were measured. We checked the activation of CTLs by flow cytometry. Patients were treated by percutaneous coronary intervention within 12 hours after onset. Successful myocardial reperfusion (TIMI flow grade 2 or 3) was accomplished in all patients. LV end-diastolic volume index (LVEDVI) was calculated on day 1 and 6 months after onset. Results: Plasma levels of TNFα, sFasL and granzyme B increased significantly after the onset of AMI (TNFα; day 1: 1.6±0.47, day 7: 3.3±0.65, day14: 4.0±1.2 pg/ml, p<0.05, sFasL; day 1: 72±5.2, day 7: 86±6.7, day14: 95±7.3 pg/ml, p<0.05, granzyme B; day 1: 63±18.4, day 7: 283±57.8, day14: 210.9±46.3 pg/ml, p<0.001). The percentage of CD69± to CD3+ CD8+ lymphocytes was significantly increased (CD69+/CD3+ CD8+; day 1: 14.5±1.7, day 7: 15.8±1.2, day 14: 19.1±1.4%, p<0.05), suggesting that CTLs were activated after onset. Univariate regression analysis showed a significant positive correlation between plasma granzyme B level on day 14 and fold-increase in LVEDVI (r=+0.45, p<0.01). No significant correlation was observed between TNFα and changes in LVEDVI, or sFasL and changes in LVEDVI. Stepwise multivariate regression analysis showed that the plasma granzyme B level on day 14 is a significant explanatory variable for changes in LVEDVI (β = +0.53, p<0.001). Conclusions: These results first indicate that among proapoptic molecules, granzyme B has a critical role in the progression of LV remodeling after AMI.

Abstract 566: Critical Role of Ghrelin in Ventricular Remodeling after Acute Myocardial Infarction

Background: Ghrelin is a novel growth hormone (GH)-releasing peptide, originally isolated from the stomach, which has been identified as an endogenous ligand for the GH secretagogues receptor (GHS-R). Previous studies revealed that chronic administration of ghrelin suppresses cardiac sympathetic activity and prevents left ventricular (LV) remodeling after acute myocardial infarction (AMI). However clinical role of ghrelin after AMI is still not clear. We examined the role of ghrelin in LV remodeling after AMI. Objectives: To elucidate the role of ghrelin in LV remodeling after AMI. Subjects and methods: We employed patients with the first AMI (n=41, mean age 61.9±8.9 years old). We obtained peripheral blood on 1, 7, 14 days and 6 months after the onset. Plasma total ghrelin levels were measured by enzyme-linked immunosorbent assay. Patients were treated by percutaneous coronary intervention within 12 hours after onset. Successful myocardial reperfusion (TIMI flow grade 2 or 3) was accomplished in all patients. To analyze LV remodeling, all patients submitted to two serial left ventriculographies carried out on the day of admission and 6 months after the onset (mean 199±13 days). LV volume index (LVEDVI) was calculated by QCA-CMS software. Results: Plasma total ghrelin levels increased after the onset of AMI (day 0: 28.4±6.4, day 7: 75.1±12.2, day 14: 89.9±14.8 pg/ml, 6months: 46.5±6.6 fmol/ml, p<0.001). There was a significant positive correlation between plasma ghrelin levels on day 14 after the onset and changes in LVEDVI (r=+0.53, p<0.001). The stepwise multivariate regression analysis showed that the plasma ghrelin level on day 14 is a significant explanatory variable for the changes in LVEDVI (F=8.77, p<0.01, β=+0.40). Conclusions: The elevation of Ghrelin levels might be a compensatory mechanism to prevent LV remodeling. These results first indicate that ghrelin has a critical role in the progression of left ventricular remodeling after AMI.

Abstract 1770: Proteasome Switching is Associated with Adverse Cardiac Remodeling in a Transgenic Mouse Model of Sustained Inflammatory Signaling

The 26S proteasome possess proteolytic activity and deubiquitinating (DUB) activity of ubiquitin tagged proteins. Whereas the proteolytic activity of the 26S proteasome facilitates protein degradation, proteasome DUB activity spares proteins from degradation by shortening the length of the ubiquitin chains, thereby preventing proteins from being degraded by the 26S proteasome. In yeast, increased DUB activity is beneficial by preventing depletion of ubiquitin pools critical for cell signaling. However, the role of DUB activity in mammalian systems is not known. We have shown that mice with cardiac restricted overexpression of tumor necrosis factor (sTNF mice) develop a heart failure phenotype characterized by progressive left ventricular (LV) remodeling and accumulation of pro-apoptotic proteins, including Smac/Diablo. To determine whether the adverse LV remodeling in sTNF mice was related to alterations in DUB activity we measured the cleavage of ubiquitin-AMC, an in vitro fluorescent substrate for DUBs, in purified preparations of the 26S proteasome obtained from hearts of 4 week old sTNF and littermate (LM) control mice. Compared to LM controls we observed a significant (p < 0.001) 60.8% decrease in activity of the 26S proteasome and a significant (p < 0.01) 24.2% increase in DUB activity in sTNF mouse hearts. There was also a significant (p < 0.01) 11-fold increase myocardial protein levels of USP14, a critical DUB associated with the 26S proteasome in sTNF mouse hearts. The decrease in 26S proteasome activity and increased DUB activity in sTNF mouse hearts was accompanied by an increase in myocardial levels of ubiquitinated SMAC/Diablo. Taken together these results show for the first time that sustained myocardial inflammation leads to switch in the function of the proteasome from a proteolytic function to a protein sparing function. Although this “proteasome switching” may provide a short-term adaptive benefit by preventing depletion of critical ubiquitin pools, it may lead to long-term maladaptive consequences by allowing the progressive accumulation of potentially harmful pro-apoptotic proteins in the cytosol, which may in turn promote programmed cell death and adverse cardiac remodeling.

Abstract 4239: Speckle Tracking Imaging Detects Sub-Clinical Myocardial Dysfunction in Asymptomatic Patients with Type 2 Diabetes Mellitus

Diabetic cardiomyopathy, a major complication of diabetes mellitus (DM), is preceded by a silent phase of progressive left ventricular (LV) remodeling. Our aim was to evaluate whether speckle tracking imaging (STI) was able to detect early, sub-clinical myocardial dysfunction in a population of asymptomatic type II DM patients with no signs or history of heart disease and a normal conventional echo . 114 patients with type II DM (52 ± 4 years, 45 females, HbA1c 7.7 ± 1.4%) and 88 age-matched healthy volunteers (HV) without any cardiovascular risk factor (52 ± 3 years, 58 females) underwent a conventional and STI echocardiography (Vivid 7, GE). Mean longitudinal strain (S L ) was assessed from the basal, mid and apical segments of the myocardial walls in apical 2- and 4-chamber views. Mean radial strain (S R ) was calculated from the short-axis view at the midventricular level. Univariate and multivariate regression analyses were used to identify the parameters contributing to the difference in S L and S R between the 2 groups. Variables used for analysis were as follows: DM, gender, BMI, systolic (sBP) and diastolic blood pressure (dBP), heart rate, IVSd and PWd thickeness, LV end-diastolic (LVEDD) and end-systolic diameters (LVESD). Clinical, conventional echo and STI parameters in the 2 groups are summurized in the table . On univariate analysis, factors associated with a significant lower strain in type II DM patients were: DM, male gender, BMI, sBP and dBP for S L and DM, sex and LVESD for S R (p<0.05 for all). On multiple regression analysis, the only factors accociated with a significant decrease in strain in the DM group were DM (p = 0.005) and male gender (p = 0.008) for S L and DM (p = 0.01) for S R . STI is able to early detect subclinical myocardial dysfunction in a population with Type II DM. This decrease in S L and S R might be considered as a preclinical marker of diabetic cardiomyopathy.

Direct Renin Inhibition

The process of cardiac healing and recovery after an acute myocardial infarction encompasses profound changes in the necrotic area (“infarct zone”), in the neighboring ischemic zone (“area at risk”), and in the nonischemic myocardium (“nonischemic region”). Patient’s prognosis ultimately depends on the functional, biochemical, electric, and structural changes taking place in these 3 different areas as a consequence of the acute ischemic event. These extracellular, cellular, and subcellular events are globally referred to as “postinfarction remodeling,” and therapeutic interventions able to slow or reverse its progression have a favorable impact on patient prognosis.1 A pivotal role in these processes is played by the renin-angiotensin-aldosterone system (RAAS) that is undoubtedly hyperactivated after myocardial infarction, together with other neural and endocrine systems. Locally synthesized angiotensin II has been suggested to act as an autocrine, paracrine, and intracrine modulator of cardiac function.2 Notably, the major components of the RAAS components have been shown in cardiac tissue, and extracardiac renin uptake is associated with local release by myocardial mast cells.3 Angiotensin II intracellular signal transduction involves the phosphorylation of several proteins, such as membrane transporters and selective ion channels, structural and contractile proteins, and enzymes that regulate metabolism, protein synthesis, and gene expression. These multiple actions are mediated via complex intracellular signaling pathways, including stimulation of the phospholipase C-inositol 1,4,5-trisphosphate-1,2-diacylglycerol cascade, mitogen-activated protein kinases, tyrosine kinases, RhoA/Rho kinase, and reactive oxygen species generation through vascular NADPH oxidase activation. Beyond directly affecting vasomotor tone, angiotensin II potentiates the effects of several vasoconstrictor hormones, facilitates the central and …

Left ventricular systolic dyssynchrony is a predictor of cardiac remodeling after myocardial infarction

We sought to determine whether early assessment of left ventricular (LV) dyssynchrony by tissue Doppler imaging may predict progressive ventricular enlargement and cardiac dysfunction after acute myocardial infarction (MI). Forty-seven patients (mean age 59.9 +/- 11.6 years) with normal QRS duration underwent tissue Doppler imaging and contrast-enhanced cardiac magnetic resonance imaging (Ce-MRI) at days 2 to 6, 3 months, and at 1 year after the index MI. Systolic dyssynchrony index (Ts-SD) was calculated from 12 LV segments, and infarct size (IS) by Ce-MRI. The remodeling group (n = 16) (defined as an increase in end-systolic volume > or =10% between 1 year and baseline) had greater initial IS (27.2 +/- 9.6 vs 13.7 +/- 4.1%, P < .001) and Ts-SD (50.9 +/- 12.8 vs 33.6 +/- 7.7 milliseconds, P < .001) than nonremodeling group (n = 31). At 1 year, the remodeling group had progressive increase in Ts-SD and decrease in LV ejection fraction (57.3 +/- 18.5 and 36.0 +/- 7.6%, respectively; both P < .05 vs baseline). Both Ts-SD (odds ratio 1.19 [1.07-1.32], P = .001) and IS (odds ratio 1.65 [1.19-2.29], P = .003) were shown to be independent predictors of progressive LV remodeling. A cutoff value of Ts-SD > or =45 milliseconds predicted LV remodeling at 1 year (sensitivity 90.5%, specificity 90.9%, Area-under-curve 0.907) (P = .0005). Left ventricular systolic dyssynchrony is a newly identified predictor of chronic LV remodeling after acute MI, which is independent and incremental to conventional assessment and IS as measured by Ce-MRI.

Darbepoetin-alpha prevents progressive left ventricular dysfunction and remodeling in nonanemic dogs with heart failure.

In anemic patients with heart failure (HF), erythropoietin-type drugs can elicit clinical improvement. This study examined the effects of chronic monotherapy with darbepoetin-alpha (DARB) on left ventricular (LV) function and remodeling in nonanemic dogs with advanced HF. HF [LV ejection fraction (EF) approximately 25%] was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to once a week subcutaneous injection of DARB (1.0 microg/kg, n=7) or to no therapy (HF, n=7). All procedures were performed during cardiac catheterization under general anesthesia and under sterile conditions. LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF were measured before the initiation of therapy and at the end of 3 mo of therapy. mRNA and protein expression of caspase-3, hypoxia inducible factor-1alpha, and the bone marrow-derived stem cell marker c-Kit were determined in LV tissue. In HF dogs, EDV and ESV increased and EF decreased after 3 mo of followup. Treatment with DARB prevented the increase in EDV, decreased ESV, and increased EF. DARB therapy also normalized the expression of HIF-1alpha and active caspase-3 and enhanced the expression of c-Kit. We conclude that chronic monotherapy with DARB prevents progressive LV dysfunction and dilation in nonanemic dogs with advanced HF. These results suggest that DARB elicits beneficial effects in HF that are independent of the presence of anemia.

Effects of Benidipine, a Calcium Antagonist, on the progression of left ventricular remodeling in a Murine Model of Dilated Cardiomyopathy

Effects of Benidipine, a Calcium Antagonist, on the progression of left ventricular remodeling in a Murine Model of Dilated Cardiomyopathy

Ranolazine combined with enalapril or metoprolol prevents progressive LV dysfunction and remodeling in dogs with moderate heart failure

Acute intravenous infusion of ranolazine (Ran), an anti-ischemic/antiangina drug, was previously shown to improve left ventricular (LV) ejection fraction (EF) without a concomitant increase in myocardial oxygen consumption in dogs with chronic heart failure (HF). This study examined the effects of treatment with Ran alone and in combination with metoprolol (Met) or enalapril (Ena) on LV function and remodeling in dogs with HF. Dogs (n = 28) with microembolization-induced HF were randomized to 3 mo oral treatment with Ran alone [375 mg twice daily (bid); n = 7], Ran (375 mg bid) in combination with Met tartrate (25 mg bid; n = 7), Ran (375 mg bid) in combination with Ena (10 mg bid; n = 7), or placebo (PL; Ran vehicle bid; n = 7). Ventriculographic measurements of LV end-diastolic volume (EDV) and end-systolic volume (ESV) and LV EF were obtained before treatment and after 3 mo of treatment. In PL-treated dogs, EDV and ESV increased significantly. Ran alone prevented the increase in EDV and ESV seen in the PL group and significantly increased EF, albeit modestly, from 35 +/- 1% to 37 +/- 2%. When combined with either Ena or Met, Ran prevented the increase in EDV, significantly decreased ESV, and markedly increased EF compared with those of PL. EF increased from 35 +/- 1% to 40 +/- 1% with Ran + Ena and from 34 +/- 1% to 41 +/- 1% with Ran + Met. Ran alone or in combination with Ena or Met was also associated with beneficial effects at the cellular level on histomorphometric parameters such as hypertrophy, fibrosis, and capillary density as well as the expression for pathological hypertrophy and Ca2+ cycling genes. In conclusion, Ran prevented progressive LV dysfunction and global and cellular myocardial remodeling, and Ran in combination with Ena or Met improved LV function beyond that observed with Ran alone.

Sleep apnea in systolic heart failure: Update on prevalence, impact and therapy

Systolic heart failure is a highly prevalent disorder associated with excess morbidity and mortality. In spite of recent TRIUMPHS in the classic pharmacological therapy of heart failure, the disorder continues to be associated with excess mortality. This suggests the presence of residual factors, which contribute to the progression of left ventricular remodeling. It is likely that identification of these factors and appropriate therapy could further improve the survival of patients with systolic heart failure.

Regional remodeling strain and its association with myocardial apoptosis after myocardial infarction in an ovine model

Progressive left ventricular remodeling after myocardial infarction has been viewed as an important contributor to progressive heart failure. The objective of this study was to investigate the relationship between myocardial apoptosis and strain during progressive cardiac remodeling. Before creation of an anterolateral left ventricular infarction by ligation of diagonal arteries, 16 sonomicrometry transducers were placed in the left ventricular free wall of 8 sheep to assess regional deformation in the infarct, adjacent, and normally perfused remote myocardial regions over 8 weeks' duration. Hemodynamic, echocardiographic and sonomicrometric data were collected before infarction and then 30 minutes and 2, 6, and 8 weeks after infarction. At the end of the study, regional myocardial tissues were collected for apoptotic signaling proteins. At terminal study, an increase in left ventricular end-diastolic pressure of 8.1 +/- 0.1 mm Hg, a decrease in ejection fraction from 54.19% +/- 5.68% to 30.55% +/- 2.72%, and an end-diastolic volume increase of 46.08 +/- 5.02 mL as compared with the preinfarct values were observed. The fractional contraction at terminal study correlated with the relative abundance of apoptotic protein expressions: cytochrome c (r(2) = 0.02, P < .05), mitochondrial Bax (r(2) = 0.27, P < .05), caspase-3 (r(2) = 0.31, P < .05), and poly (adenosine diphosphate-ribose) polymerase (r(2) = 0.30, P < .05). These myocardial apoptotic activities also correlated with remodeling strain: cytochrome c (r(2) = 0.02, P < .05), mitochondrial Bax (r(2) = 0.28, P < .05), caspase-3 (r(2) = 0.43, P < .05), and poly (adenosine diphosphate-ribose) polymerase (r(2) = 0.37, P < .05). Increase in regional remodeling strain led to an increase in myocardial apoptosis and regional contractile dysfunction in heart failure.

Beneficial Effect of the Central Nervous System β-Adrenoceptor Blockade on the Failing Heart

Heart failure patients are routinely given beta-adrenoceptor antagonists (beta-blockers), although the mechanism(s) underlying their beneficial effects is not fully resolved. It is not entirely clear how long-term application of negative inotropic compounds improves cardiac performance, slows remodeling processes, and decreases mortality. All beta-blockers, which produce a beneficial effect in heart failure, have in common a high degree of lipophilicity and, therefore, have the ability to cross the blood-brain barrier. Here, we show that blockade of beta-adrenoceptors directly in the brain (chronic intracerebroventricular administration of metoprolol) attenuates the progression of left ventricular remodeling in a rat model of myocardial infarction-induced heart failure. These results provide the first direct evidence that the action of certain beta-blockers in the brain could contribute to their beneficial effect on the failing heart.

Clinical Implications of Early Mitral Regurgitation in Patients With Reperfused Acute Myocardial Infarction

Background The mechanisms by which mitral regurgitation (MR) may lead to an adverse prognosis after reperfused acute myocardial infarction (AMI) have not been fully investigated. We hypothesized that in the early phase of ST-elevation AMI, MR may lead to progressive left ventricular (LV) remodeling and subsequent heart failure. Methods and Results A series of 184 patients with AMI successfully treated with primary angioplasty underwent serial two-dimensional echocardiography at admission, at 1 and 6 months, and at 6-month angiography. The mean follow-up was 18 ± 7 months. On the basis of color Doppler, MR was graded from 0 (none) to 4 (severe). Patients were divided into group 1 (n = 146) with an MR grade of ≤ 1 and group 2 (n = 38) with an MR grade of ≥ 2. The regurgitant volume and effective regurgitant orifice area of MR were significantly higher in group 2 than in group 1 (36.7 ± 12.9 mL/beat vs 4.67 ± 3.2 mL/beat, P < .0001; 22.5 ± 7.6 mm 2 vs 5.8 ± 5.7 mm 2, P < .0001, respectively). LV end-diastolic volume progressively increased in group 2 and was significantly higher than in group 1 at 6 months (113.8 ± 31.8 mL vs 96.9 ± 34.1 mL, P = .0002), with a higher prevalence of LV remodeling (66% vs 22%, P < .0001). At 2 years, the incidence of heart failure was higher in group 2 than in group 1 (39% vs 12%, P < .0002). A significant correlation was found between effective regurgitant orifice area of MR and baseline to 6-month change of LV end-diastolic volume ( P = .001). By stepwise multivariate regression analysis effective regurgitant orifice area of early MR was an independent predictor of LV remodeling ( P = .001) and late heart failure (hazard ratio: 1.069, 95% confidence interval 1.033–1.106, P < .0001, Cox analysis). Conclusion In reperfused AMI, early high-degree MR is an important predictor of both LV dilation and subsequent heart failure.

Stunning, Hibernation, and Assessment of Myocardial Viability

The last 3 decades have witnessed an unprecedented improvement in the outcome of patients with acute coronary syndromes. The widespread use of thrombolytic therapy and percutaneous coronary interventions, in association with increasingly potent antithrombotic agents, has contributed to significant reductions in mortality and morbidity in these patients. Although overall survival has improved, a downside of this success has been the greater number of patients with residual left ventricular (LV) dysfunction undergoing progressive LV remodeling and congestive heart failure. This problem is compounded by the rising age of our population and the higher prevalence of comorbidities such as diabetes mellitus that confer an increased risk of coronary artery disease (CAD) and congestive heart failure. Patients with CAD represent by far the most numerous cohort among those with congestive heart failure, and their treatment remains a partial success.1 Typically, these patients have multivessel disease, increased LV volumes, and variable degrees of regional and/or global systolic dysfunction, although more cases of isolated diastolic dysfunction have been reported recently.2–4 In these patients, coronary revascularization may lead to symptomatic and prognostic improvement, and these clinical benefits are accompanied by evidence of reverse LV remodeling. In this context, the concept of myocardial viability was developed and a number of different techniques have been used to demonstrate the presence of viable tissue before coronary revascularization. The aim of this review article is to summarize our current understanding of the concept of myocardial viability and its clinical implications in patients with CAD and chronic LV dysfunction. Throughout this review, we use the term viability to describe dysfunctional myocardium subtended by diseased coronary arteries with limited or absent scarring that therefore has the potential for functional recovery. Viability is a prospective definition, but it does not imply evidence of functional recovery after interventions. The term hibernation, which …

Recent Patents on Cardiovascular Stem Cells

Chronic heart failure has emerged as a leading cause of morbidity and mortality worldwide. Conceptually, replacement of akinetic scar tissue by viable myocardium and improvement of neovascularization should improve cardiac function and impede progressive left ventricular remodelling. Experimental and clinical studies suggest that transfer or mobilization of stem and progenitor cells can have a favourable impact on tissue perfusion and contractile cardiac performance. The aim of the present review was to screen various available patent data bases to give an overview on different patent applications of cell-based and non-cell based therapies in regenerative cardiovascular medicine. The first part describes cell based methods and use of growth factors to improve cardiovascular function. Secondly, patents on methods to improve angiogenesis, re-endothelialization and vascular function are presented. Finally, we describe patents describing methods for improved differentiation of stem cells to cardiovascular cells, including the generation of cardiomyocytes from embryonic or adult stem cells. A systematic overview on the current patent situation about use of stem cells in cardiovascular medicine should facilitate future decision making in the development of novel therapeutic strategies in regenerative medicine.

Comparative effects of torasemide and furosemide in rats with heart failure

It has been reported that torasemide but not furosemide, may block the renin–angiotensin–aldosterone system and therefore it might attenuate myocardial remodeling accompanied by left ventricular (LV) dysfunction. We therefore compared the therapeutic effects of torasemide, a long-acting loop diuretic, and furosemide, a short-acting one, on the progression of LV remodeling in a rat model of chronic heart failure (CHF) after experimental autoimmune myocarditis (EAM). CHF was elicited in Lewis rats by immunization with porcine cardiac myosin. Twenty-eight days after immunization, rats were treated for 28 days with torasemide, furosemide, or vehicle. We investigated the effects on metabolic and neurohumoral parameters, cardiac fibrosis and remodeling in EAM rats. Diuresis was increased dose dependently by both torasemide and furosemide, showed an equipotent natriuretic effect. The urinary potassium excretion was significantly increased with furosemide in comparison to torasemide. Myocardial functional parameters were significantly improved by torasemide. Conversely, these parameters did not change in rats receiving furosemide. Torasemide suppressed LV fibrosis, myocardial protein levels of transforming growth factor-beta1, collagen III, and aldosterone synthase and improved survival rate to the control level, but furosemide did not. Moreover, both pharmacological interventions significantly elevated plasma angiotensin II and decreased atrial natriuretic peptide in a dose-dependent manner. Our results demonstrate that compared with furosemide, torasemide treatment significantly improved survival rate, LV function and ameliorated the progression of cardiac remodeling in rats with CHF after EAM.

Baseline characteristics of patients recruited in the AREA IN-CHF study (Antiremodelling Effect of Aldosterone Receptors Blockade with Canrenone in Mild Chronic Heart Failure)

Excess aldosterone activity contributes to the pathogenesis and progression of heart failure (HF). Aldosterone antagonists improve clinical outcome in patients with severe HF or left ventricular (LV) dysfunction after myocardial infarction, but knowledge of their impact in mild chronic HF is sparse. AREA IN-CHF was planned to investigate the effects of canrenone on progression of LV remodelling in mild HF. AREA IN-CHF is a multicentre, randomised, double-blind, parallel group comparison of canrenone (up to 50 mg/day) versus placebo in mild stable HF. The primary endpoint is change in echocardiographic LV end-diastolic volume over 12 months. Patients had New York Heart Association class II HF, LV ejection fraction < or =45%, stable standard therapy, creatinine < or =2.5 mg/dl, potassium < or =5.0 mmol/l. Follow-up examinations were scheduled monthly for the first 3 months and every 3 months thereafter. Aldosterone was measured at baseline, brain natriuretic peptide and procollagen type III amino-terminal peptide (PIIINP) at baseline and at 6 months. Echocardiography was performed at baseline, at 6 and 12 months. Among 467 patients, median age 64 years (interquartile range (IQR) 56-70 years), 84% were men, 52% had ischaemic HF, 96% were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 79% beta-blockers. Brain natriuretic peptide, aldosterone and PIIINP were 88 pg/ml (IQR 35-185 pg/ml), 118 pg/ml (IQR 75-177 pg/ml), and 5.38 microg/l (IQR 3.98-7.14 microg/l), respectively. LV end-diastolic volume was 79 ml/m (IQR 64-105 ml/m) and LV ejection fraction was 40% (IQR 33-45%). The role of aldosterone blockade in patients with mild HF remains to be established. AREA IN-CHF is addressing this issue in a large population on optimal medical therapy.

Drug Insight: aldosterone-receptor antagonists in heart failure—the journey continues

Aldosterone is an important mediator in the pathogenesis of heart failure, and increased plasma aldosterone levels are associated with a poor prognosis. Aldosterone-receptor blocking drugs can slow the progression of left ventricular remodeling and reduce the occurrence of sudden cardiac death. Two widely publicized clinical trials provide data demonstrating survival benefits with spironolactone and eplerenone in chronic and postinfarction heart failure. The publication of these trials has generated widespread enthusiasm for spironolactone and eplerenone, leading to the more frequent and sometimes unbridled use of these drugs in the medical community. We herein describe the likely mechanisms of action of aldosterone-receptor antagonists, discuss the existing clinical evidence supporting their use, and provide practical advice on their use in the management of patients with heart failure.

Heart Failure and Its Management With β‐Blockade: Potential Applications of Once‐Daily Therapy

Heart failure (HF) due to left ventricular (LV) systolic dysfunction is a progressive disease beginning with a primary injury that activates compensatory cardiovascular mechanisms including varying degrees of neurohormonal activation. Within the neurohormonal cascade, activation of the sympathetic nervous system is in part responsible for ongoing myocardial injury, progressive LV remodeling, and functional deterioration eventually leading to symptomatic HF. Large randomized clinical trials of certain β‐blockers added to standard therapies have shown unequivocal benefits in patients with chronic systolic HF resulting in reduced remodeling, fewer total and cardiovascular deaths, and less risk of hospitalization for worsening HF. Evidence‐based clinical guidelines recommend β‐blockers as part of the regimen for patients with systolic HF as well as LV dysfunction following myocardial infarction. Based on published clinical trial results, bisoprolol, carvedilol, and sustained‐release metoprolol succinate are recommended for systolic HF. Carvedilol, propranolol, and timolol are recommended for post‐myocardial infarction LV dysfunction. Unfortunately, these evidence‐based therapies are often underused in actual practice. Various strategies to increase β‐blocker use in HF have been attempted, including in‐hospital initiation of β‐blocker therapy. Simplifying dosing regimens may also improve adherence to prescribed medications. Use of controlled‐release carvedilol may encourage better adherence in patients with LV dysfunction and help overcome at least one barrier to optimal evidence‐based care.

Effects of surgery on ischaemic mitral regurgitation: A prospective multicenter registry (SIMRAM registry)

Functional ischaemic mitral regurgitation (IMR) is common in patients with ischaemic left ventricular dysfunction undergoing coronary artery bypass surgery. Although the presence of IMR negatively affects prognosis, the additional benefit of valve repair is debated, particularly with mild IMR at rest. Exercise echocardiography may help identify a subset of patients at higher risk of cardiovascular events by revealing the dynamic component of IMR. A large prospective, multicentre, non-randomized registry is designed to evaluate the effects of surgery on IMR at rest and on its dynamic component at exercise (z). SIMRAM will enrol approximately 550 patients with IMR in up to 17 centres with clinical and exercise follow-up for 1 year. Three sets of outcomes will be prospectively assessed and several hypotheses will be tested including determinants of adverse outcome and progressive left ventricular remodeling, efficacy of treatment and role of ischaemia on the dynamic consequences of IMR. Enrolment began in November 2006 and is expected to end by early 2008.