Controlled Rosuvastatin Multinational Trial In Heart Failure Research Articles

Assessing the Role of Rare Genetic Variation in Patients With Heart Failure

Sequencing studies have identified causal genetic variants for distinct subtypes of heart failure (HF) such as hypertrophic or dilated cardiomyopathy. However, the role of rare, high-impact variants in HF, for which ischemic heart disease is the leading cause, has not been systematically investigated. To assess the contribution of rare variants to all-cause HF with and without reduced left ventricular ejection fraction. This was a retrospective analysis of clinical trials and a prospective epidemiological resource (UK Biobank). Whole-exome sequencing of patients with HF was conducted from the Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) and Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) clinical trials. Data were collected from March 1999 to May 2003 for the CHARM studies and September 2003 to July 2007 for the CORONA study. Using a gene-based collapsing approach, the proportion of patients with HF and controls carrying rare and presumed deleterious variants was compared. The burden of pathogenic variants in known cardiomyopathy genes was also investigated to assess the diagnostic yield. Exome sequencing data were generated between January 2018 and October 2018, and analysis began October 2018 and ended April 2020. Odds ratios and P values for genes enriched for rare and presumed deleterious variants in either patients with HF or controls and diagnostic yield of pathogenic variants in known cardiomyopathy genes. This study included 5942 patients with HF and 13 156 controls. The mean (SD) age was 68.9 (9.9) years and 4213 (70.9%) were male. A significant enrichment of protein-truncating variants in the TTN gene (P = 3.35 × 10-13; odds ratio, 2.54; 95% CI, 1.96-3.31) that was further increased after restriction to variants in exons constitutively expressed in the heart (odds ratio, 4.52; 95% CI, 3.10-6.68). Validation using UK Biobank data showed a similar enrichment (odds ratio, 4.97; 95% CI, 3.94-6.19 after restriction). In the clinical trials, 201 of 5916 patients with HF (3.4%) had a pathogenic or likely pathogenic cardiomyopathy variant implicating 21 different genes. Notably, 121 of 201 individuals (60.2%) had ischemic heart disease as the clinically identified etiology for the HF. Individuals with HF and preserved ejection fraction had only a slightly lower yield than individuals with midrange or reduced ejection fraction (20 of 767 [2.6%] vs 15 of 392 [3.8%] vs 166 of 4757 [3.5%]). An increased burden of diagnostic mendelian cardiomyopathy variants in a broad group of patients with HF of mostly ischemic etiology compared with controls was observed. This work provides further evidence that mendelian genetic conditions may represent an important subset of complex late-onset diseases such as HF, irrespective of the clinical presentation.

Low YKL-40 in chronic heart failure may predict beneficial effects of statins: analysis from the controlled rosuvastatin multinational trial in heart failure (CORONA)

Context and objective: To evaluate if YKL-40 can provide prognostic information in patients with ischemic heart failure (HF) and identify patients who may benefit from statin therapy.Materials and methods: The association between serum YKL-40 and predefined outcome was evaluated in 1344 HF patients assigned to rosuvastatin or placebo.Results: YKL-40 was not associated with outcome in adjusted analysis. In YKL-40 tertile 1, an effect on the primary outcome (HR 0.50, p = 0.006) and CV death (HR 0.54, p = 0.040) was seen by rosuvastatin in adjusted analysis.Conclusions: A beneficial modification of outcome was observed with statin therapy in patients with low YKL-40 levels.

Loop diuretics, renal function and clinical outcome in patients with heart failure and reduced ejection fraction.

We aimed to study the relationships of loop diuretic dose with renal function and clinical outcomes in patients with chronic heart failure (HF). Loop diuretic dose at baseline was recorded in patients included in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). The relationship to change in estimated glomerular filtration rate (eGFR) over time and to the first occurrence of the composite outcome of cardiovascular (CV) death or hospitalization owing to HF was examined in propensity score matched cohorts. Of the 5011 patients, 2550, 745, and 449 were receiving >80 mg (high), 41-80 mg (medium) and ≤40 mg (low) of loop diuretics in furosemide equivalent daily dosages, respectively, which were used to assemble 229, 385, and 1045 pairs of propensity-matched high, medium, and low dose cohorts. Compared with matched no loop diuretic groups, eGFR declined 0.3 ± 0.2, 0.3 ± 0.3 and 1.2 ± 0.5 mL/min/1.73 m(2) /year in the low-, medium-, and high-dose groups, respectively. Compared with matched no loop diuretic groups, hazard ratios (HR) (95% confidence intervals) for outcome associated with low-, medium- and high-dose groups were 1.71 (1.41-2.06), 1.99 (1.50-2.64), and 2.94 (1.95-4.41), respectively. Higher loop diuretic dose was particularly associated with increased risk for hospitalization owing to HF: HR 4.80 (2.75-8.37), P < 0.001. The use of loop diuretics was associated with a slightly greater rate of decline in eGFR, which did not vary significantly by diuretic dose.Loop diuretic dose was associated with higher risks of (CV) mortality and predominantly hospitalization owing to HF, which appeared to be higher among those receiving higher daily doses.

Secreted Frizzled Related Protein 3 in Chronic Heart Failure: Analysis from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA).

BackgroundWe have previously demonstrated an association between increased sFRP3 expression and adverse outcome in a population of HF irrespective of cause and left ventricular ejection fraction. In this study we evaluated the prognostic value of sFRP3 in older patients with chronic systolic HF of ischemic origin.MethodsWe evaluated sFRP3, by tertiles, as a risk factor for the primary endpoint (cardiovascular [CV] mortality, nonfatal myocardial infarction, nonfatal stroke), all-cause mortality, CV mortality, death from worsening HF (WHF), any coronary event, including sudden death, as well as hospitalizations for CV causes and WHF in 1444 patients from the CORONA population, randomly assigned to 10 mg rosuvastatin or placebo.ResultsKaplan-Meier curves for the primary endpoint, as well as all-cause- and CV mortality revealed a markedly better survival for patients with sFRP3 levels in the middle tertile of compared to the 1st and 3rd tertile. In multivariable Cox-regression, after full adjustment including high-sensitive CRP and NT-proBNP, a lower event rate for the primary end point, all cause and CV mortality was observed for patients with tertile 2 sFRP3 levels (HR 0.57 [0.44–0.74], 0.55 [0.44–0.74] and 0.52 [0.39–0.69]; p<0.001), as well as for the number of coronary events (HR 0.62 [0.47–0.82], p = 0.001) and sudden death (HR 0.55 [0.37–0.82], p = 0.002). Applying sFRP3 values to the fully adjusted regression model resulted in highly significant continuous net reclassification improvements for the primary endpoint, all cause and CV mortality, coronary events and sudden death (range 0.24–0.31; p≤0.002 for all).ConclusionsIntermediate serum sFRP3 levels are associated with better survival and fewer CV events than low or high sFRP3 levels, independently of conventional risk factors, in older patients with chronic systolic HF of ischemic origin. Our study suggests that balanced Wnt activity might confer protective effects in a clinical HF setting.Trial Registration http://www.clinicaltrials.gov NCT00206310

March 2015 at a glance.

March 2015 at a glance.

Telomere length and outcomes in ischaemic heart failure: data from the COntrolled ROsuvastatin multiNAtional Trial in Heart Failure (CORONA).

Leucocyte telomere length is considered a marker of biological ageing and has been suggested to be shorter in patients with CAD and heart failure compared with healthy controls. The aim of this study was to determine whether telomere length is associated with clinical outcomes in patients with ischaemic heart failure and whether this association is superior to chronological age as defined by date of birth. We measured leucocyte telomere length in 3275 patients with chronic ischaemic systolic heart failure participating in the COntrolled ROsuvastatin multiNAtional Trial in Heart Failure (CORONA) study. The primary composite endpoint was cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, which occurred in 575 patients during follow-up. We observed a significant association of leucocyte telomere lengths with the primary endpoint (hazard ratio 1.10; 95% confidence interval 1.01-1.20; P=0.03). However, this observation was not superior to age as defined by date of birth. The neutral effect of rosuvastatin treatment on clinical outcomes was not modified by baseline telomere length. Biological age as defined by leucocyte telomere length was associated with clinical outcomes in patients with ischaemic heart failure, but this association did not add prognostic information above age as defined by date of birth.

The impact of coronary artery disease risk loci on ischemic heart failure severity and prognosis: association analysis in the COntrolled ROsuvastatin multiNAtional trial in heart failure (CORONA).

BackgroundRecent genome-wide association studies have identified multiple loci that are associated with an increased risk of developing coronary artery disease (CAD). The impact of these loci on the disease severity and prognosis of ischemic heart failure due to CAD is currently unknown.MethodsWe undertook association analysis of 7 single nucleotide polymorphism (rs599839, rs17465637, rs2972147, rs6922269, rs1333049, rs501120, and rs17228212) at 7 well established CAD risk loci (1p13.3, 1q41, 2q36.3, 6q25.1, 9p21.3, 10q11.21, and 15q22.33, respectively) in 3,320 subjects diagnosed with systolic heart failure of ischemic aetiology and participating in the COntrolled ROsuvastatin multiNAtional Trial in Heart Failure (CORONA) trial. The primary outcome was the composite of time to first event of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, secondary outcomes included mortality and hospitalization due to worsening heart failure.ResultsNone of the 7 loci were significantly associated with the primary composite endpoint of the CORONA trial (death from cardiovascular cases, nonfatal myocardial infarction, and nonfatal stroke). However, the 1p13.3 locus (rs599839) showed evidence for association with all-cause mortality (after adjustment for covariates; HR 0.74, 95%CI [0.61 to 0.90]; P = 0.0025) and we confirmed the 1p13.3 locus (rs599839) to be associated with lipid parameters (total cholesterol (P = 1.1x10−4), low-density lipoprotein levels (P = 3.5 × 10−7) and apolipoprotein B (P = 2.2 × 10−10)).ConclusionGenetic variants strongly associated with CAD risk are not associated with the severity and outcome of ischemic heart failure. The observed association of the 1p13.3 locus with all-cause mortality requires confirmation in further studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-014-0140-3) contains supplementary material, which is available to authorized users.

Effect of Rosuvastatin on Repeat Heart Failure Hospitalizations: The CORONA Trial (Controlled Rosuvastatin Multinational Trial in Heart Failure)

This study sought to examine the effect of statin therapy hospitalizations for heart failure (HFH) in patients in the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) trial. HFH is an important, frequently recurrent event. Conventional time-to-first event analyses do not take account repeat events. We used a number of statistical approaches to examine the effect of treatment on first and repeat HFH in the CORONA trial. In the CORONA trial, 5,011 patients ≥60 years of age with chronic New York Heart Association functional classes II to IV systolic heart failure resulting from ischemia were randomized to receive rosuvastatin or placebo. Poisson, Andersen-Gill, and negative binomial methods (NB) were used to analyze the effect of rosuvastatin on HFH, and the NB and a parametric joint frailty model (JF) were used to examine this effect while accounting for the competing risk of cardiovascular (CV) death. Rosuvastatin/placebo rate ratios were calculated, both unadjusted and adjusted. A total of 1,291 patients had 1 or more HFH (750 of these had a single HFH only), and there were a total of 2,408 HFHs. The hazard ratio for the conventional time-to-first event analysis for HFH was 0.91 (95% confidence interval [CI]: 0.82 to 1.02, p = 0.105). In contrast, the NB on repeat hospitalizations gave an unadjusted RR (RR) for HFH of 0.86 (95% CI: 0.75 to 0.99, p = 0.030), adjusted 0.82 (95% CI: 0.72 to 0.92, p = 0.001), and after including CV death as the last event, adjusted RR of 0.85 (95% CI: 0.77 to 0.94, p = 0.001). The JF gave an adjusted RR of 0.82 (95% CI: 0.73 to 0.92, p = 0.001). Similar results were found in analyses of all CV hospitalizations and all-cause hospitalizations. When repeat events were included, rosuvastatin was shown to reduce the risk of HFH by approximately 15% to 20%, equating to approximately 76 fewer admissions per 1,000 patients treated over a median 33 months of follow-up. Including repeat events could increase the ability to detect treatment effects in heart failure trials.

Fatigue as a Predictor of Outcome in Patients With Heart Failure: Analysis of CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure)

The purpose of this study was to examine the relationship between fatigue and clinical outcomes, using dyspnea as a comparator, in patients with left ventricular ejection fraction (LVEF) ≤35% enrolled in the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study. Although fatigue is a common symptom in heart failure (HF), little is known about its association with prognosis. At baseline in CORONA, fatigue "during the past few days" was measured using a 5-point exertion scale (0 = none, 1 = heavy exertion, 2 = moderate exertion, 3 = slight exertion, 4 = rest); a 4-point scale was used for dyspnea (1 to 4 as for fatigue). Patients were grouped into 3 categories: a fatigue score 0 to 1 (n = 535), fatigue score 2 (n = 1,632), and fatigue score 3 to 4 (n = 1,663); and a dyspnea score of 1 (n = 292), dyspnea score of 2 (n = 1,695), and dyspnea score of 3 to 4 (n = 1,843). The association between fatigue and dyspnea and the composite outcome of cardiovascular (CV) death or HF hospital stay and each component separately was examined using Kaplan-Meier analysis and Cox proportional-hazard models. We also examined all-cause mortality. In univariate analyses, symptom severity was associated with a higher risk of CV death or HF hospital stay (fatigue: group 3, 49% [n = 810], vs. group 1, 30% [n = 160]; dyspnea: group 3, 50% [n = 918], vs. group 1, 28% [n = 82]) and all-cause mortality (fatigue: group 3, 38% [n = 623], vs. group 1, 24% [n = 130]; dyspnea: group 3, 38% [n = 697], vs. group 1, 23% [n = 66], log-rank p < 0.0001 for all). After adjusting for other prognostic variables, including LVEF, New York Heart Association class, and N-terminal pro-B-type natriuretic peptide level, worse fatigue remained associated with higher risk of HF hospital stay but not mortality (worse dyspnea remained associated with a higher risk of both). An increase in fatigue (or dyspnea) between baseline and 6 months was also associated with worse outcomes. In HF, greater fatigue is associated with worse clinical outcomes. Closer attention should be paid to this symptom in clinical practice, with more done to standardize its measurement and understand its origins, with a view to improving treatment.

Thyroid-Stimulating Hormone and Clinical Outcomes: The CORONA Trial (Controlled Rosuvastatin Multinational Study in Heart Failure)

This study sought to examine the association between thyroid status and clinical outcomes in patients in the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study. Hypo- and hyperthyroidism were associated with worse clinical outcomes in the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial). In CORONA, 4,987 patients underwent baseline thyroid-stimulating hormone (TSH) measurement, 237 of which (4.8%) were receiving thyroid replacement therapy (TRT). Patients were classified as euthyroid (TSH: 0.3 to 5.0 μU/ml, and no TRT), hyperthyroid (<0.3 μU/ml and no TRT), or hypothyroid (>5.0 μU/ml and no TRT). The outcome composites of cardiovascular (CV) death or hospitalization for heart failure (HF), the components of this composite, and all-cause death were compared among hyperthyroid, hypothyroid, and euthyroid states, using multivariable models adjusting for previously reported prognostic variables. A total of 91.3% of patients were euthyroid, 5.0% were hypothyroid, and 3.7% were hyperthyroid. Compared with euthyroid patients, hypothyroid patients were more likely to have a history of stroke, had worse renal function and higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, were more likely to be treated with an antiarrhythmic drug (or have an implantable cardioverter defibrillator), and were less likely to smoke or be treated with a beta-blocker or angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. In univariate analyses, hypothyroidism was associated with an increased risk of the composite outcome of CV death or HF hospitalization (hazard ratio: 1.29; 95% confidence interval: 1.07 to 1.57; p = 0.008), as well as all-cause death (HR: 1.36; 95% confidence interval: 1.03 to 1.76; p = 0.004). However, after adjustment for other known predictors of outcome, the associations were weakened, and when NT-proBNP was added to the models, the association between hypothyroidism and all outcomes was eliminated. Thyroid status is not an independent predictor of outcome in heart failure with reduced ejection fraction. (Controlled Rosuvastatin Multinational Study in Heart Failure [CORONA]; NCT00206310).

Prognostic Value of Changes in Galectin-3 Levels Over Time in Patients With Heart Failure

Background— In several cross-sectional analyses, circulating baseline levels of galectin-3, a protein involved in myocardial fibrosis and remodeling, have been associated with increased risk for morbidity and mortality in patients with heart failure (HF). The importance and clinical use of repeated measurements of galectin-3 have not yet been reported. Methods and Results— Plasma galectin-3 was measured at baseline and at 3 months in patients enrolled in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) trial (n=1329), and at baseline and at 6 months in patients enrolled in the Coordinating Study Evaluating Outcomes of Advising and Counseling Failure (COACH) trial (n=324). Patient results were analyzed by categorical and percentage changes in galectin-3 level. A threshold value of 17.8 ng/mL or 15% change from baseline was used to categorize patients. Increasing galectin-3 levels over time, from a low to high galectin-3 category, were associated with significantly more HF hospitalization and mortality compared with stable or decreasing galectin-3 levels (hazard ratio in CORONA, 1.60; 95% confidence interval, 1.13–2.25; P =0.007; hazard ratio in COACH, 2.38; 95% confidence interval, 1.02–5.55; P =0.046). In addition, patients whose galectin-3 increased by &gt;15% between measurements had a 50% higher relative hazard of adverse event than those whose galectin-3 stayed within ±15% of the baseline value, independent of age, sex, diabetes mellitus, left ventricular ejection fraction, renal function, medication (β-blocker, angiotensin converting enzyme inhibitor, and angiotensin receptor blocker), and N-terminal probrain natriuretic peptide (hazard ratio in CORONA, 1.50; 95% confidence interval, 1.17–1.92; P =0.001). The impact of changing galectin-3 levels on other secondary end points was comparable. Conclusions— In 2 large cohorts of patients with chronic and acute decompensated HF, repeated measurements of galectin-3 level provided important and significant prognostic value in identifying patients with HF at elevated risk for subsequent HF morbidity and mortality.

Soluble Glycoprotein 130 Predicts Fatal Outcomes in Chronic Heart Failure

Background— Glycoprotein 130 (gp130) is the common signal-transducing receptor subunit of the interleukin-6 (IL-6) family, which may be involved in the progression of heart failure (HF). We hypothesized that soluble gp130 would provide prognostic information beyond that of IL-6 in a population with HF from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Methods and Results— The associations of soluble gp130 and IL-6 with morbidity, mortality, and mode of death were assessed by immunoassays in a subset of 1452 patients enrolled in the CORONA trial, which included patients with HF, aged ≥60 years, in New York Heart Association classes II to IV, who had ischemic heart disease and a reduced left ventricular ejection fraction. In multivariable analyses, including C-reactive protein, IL-6, troponin T, and N-terminal pro-B-type natriuretic peptide, elevated soluble gp130 (fifth quintile versus all lower quintiles) was associated with all-cause mortality (hazard ratio, 1.47 [1.11–1.93]; P =0.006), cardiovascular mortality (hazard ratio, 1.38 [1.01–1.87]; P =0.042), and death from worsening HF (hazard ratio, 1.85 [1.09–3.14]; P =0.002), but not with the primary end point (composite of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke; hazard ratio, 1.12 [0.84–1.50]; P =0.44). Plasma IL-6 was not associated with outcomes in multivariable analyses. Conclusions— Marked elevations in soluble gp130 are associated with total and cardiovascular mortality, as well as deaths from worsening HF, in elderly patients with HF of ischemic cause Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00206310.

Abstract 18355: Predictors of Fatigue in Heart Failure

Introduction Although fatigue is regarded as a prototypical symptom of heart failure (HF), little is known about its prevalence, severity and predictors. We examined which baseline characteristics predicted fatigue at baseline in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Methods CORONA enrolled 5011 patients aged ≥ 60 years with symptomatic (NYHA class II-IV), ischemic, systolic (LVEF ≤ 40%) heart failure. Fatigue “during the past few days” was measured using a five point scale: 0 none, 1 on heavy exertion, 2 moderate exertion, 3 slight exertion, 4 at rest. For the purposes of analysis, patients were grouped into 3 categories: fatigue score 0-1 (n= 588), 2 (n=1,898) and 3-4 (n= 2,525). The 3 category fatigue outcome was analyzed using ordered logistic regression, checking covariates for linearity and the proportional odds assumption. Only baseline variables that were significant (P&lt; 0.05) predictors of fatigue in univariate analyses were included in the multivariable models. Results Fatigue was reported by 96% of patients with half scoring 4 or 5 out of a possible score of 5. The baseline variables which were independent predictors of fatigue are shown in the table. NYHA class was the strongest predictor. Both atrial fibrillation/flutter and higher heart rate were predictors. Lower serum creatine kinase (CK) levels were associated with more fatigue. Adding drug therapy made little difference to the models although some treatments were additional predictors of fatigue (e.g. diuretics) whereas others (e.g. beta-blockers) were not. Notable by their absence as predictors were LVEF, blood pressure, body mass index, diabetes, renal dysfunction and NT proBNP. Discussion Fatigue was an almost universal symptom and was pronounced in many patients. Fatigue was associated with NYHA class but not measures of cardiac function (LVEF, NT proBNP). Interestingly, fatigue was associated with lower CK, probably indicative of lower muscle mass.

Personalizing Biomarker Strategies in Heart Failure With galectin-3

Heart failure is a leading cause of death and disability. Galectin-3 expression is associated with myocardial fibrosis; recombinant galectin-3 can induce myocardial fibrosis in experimental animals. However, the fact that endogenous galectin-3 is causative of myocardial fibrosis is yet to be firmly established. Nevertheless, the important discovery that N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a naturally occurring anti-inflammatory and antifibrotic peptide, inhibits galectin-3 expression, which prevents cardiac remodeling and dysfunction, provides impetus for translational research into anti-galectin therapy. The lack of a close relationship between galectin-3 and brain natriuretic peptide creates the possibility of a complimentary role. Thus, whilst brain natriuretic peptide is a useful biomarker for diagnosing heart failure, galectin-3 appears to be a culprit biomarker that mediates the development of heart failure, raising the possibility that specific anti-galectin therapy may halt the development of heart failure. Furthermore, data are beginning to emerge supporting the hypothesis that galectin-3 is crucial in the angiotensin-aldosterone pathway leading to salt and water retention, a key mechanism which can result in the development of heart failure. Thus, one might expect patients with heart failure and raised levels of galectin-3 to benefit from aldosterone antagonist therapy. Numerous clinical trials have already established the role of galectin-3 in predicting response to heart failure management, in particular how high levels of galectin-3 predicts mortality. A recent post hoc analysis of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) suggested that patients with relatively low galectin-3 levels (<19 ng/ml) are most likely to benefit from statin therapy. This generated an important hypothesis that deserves further study.

The predictive value of galectin-3 for mortality and cardiovascular events in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)

Galectin-3 is a new biomarker involved in inflammation and fibrogenesis and could therefore contribute to myocardial remodeling. We examined the prognostic value of baseline galectin-3 in a substudy involving approximately 30% of participants in the CORONA study. Patients (n = 1462) aged >60 years with systolic, ischemic heart failure (HF) were randomized to 10 mg/d rosuvastatin or placebo. The primary composite end point was cardiovascular death, nonfatal myocardial infarction, or stroke (n = 408). In the unadjusted analysis, galectin-3 was associated with all end points considered, except hospitalization for worsening of HF. In multivariable analyses, adjusting for other clinical and biochemical predictor variables, galectin-3 was significantly associated with the primary end point (hazard ratio [HR] 1.53 [1.10-2.12], P = .011) as well as all-cause (HR 1.61 [1.20-2.29], P = .002) and cardiovascular mortality (HR 1.70 [1.19-2.42], P = .003), sudden death (HR 1.83 [1.14-2.94], P = .012), and the coronary end point (HR 1.48 [1.03-2.12], P = .035). However, when N-terminal pro-brain natriuretic peptide was added to the model, galectin-3 association with the end points was markedly attenuated and no longer significant. Galectin-3 is not associated with outcome in older patients with advanced chronic systolic HF of ischemic etiology when adjusting for N-terminal pro-brain natriuretic peptide and may therefore have limited use in the prognostication of elderly patients with systolic HF in clinical practice.

Tailored therapy for heart failure: the role of biomarkers

This editorial refers to ‘Galectin-3 predicts response to statin therapy in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)’, by L. Gullestad et al. , doi:10.1093/eurheartj/ehs077 The key process leading to heart failure (HF) is cardiac remodelling in response to chronic disease stresses. Several pathways, including those that regulate cardiomyocyte hypertrophy and processes that take place outside the cardiac myocyte, e.g. in the vasculature and extracellular matrix, play important roles in the remodelling process.1 Moreover, non-cardiac pathologies, such as renal dysfunction, anaemia, and skeletal myopathy, may develop in concert with left ventricular remodelling and contribute to the functional impairment in HF. Thus, HF, truly a syndrome rather than a disease, has many distinct subtypes. The heterogeneity of the HF syndrome implies that therapies have to be tailored to the individual patient to optimize the benefits and minimize the risks of a given drug or device. European Society of Cardiology (ESC) guidelines recommend using New York Heart Association (NYHA) class, left ventricular ejection fraction, and QRS width to guide most treatment decisions in chronic HF. The degree of tailoring achieved with these recommendations is low, and, today, most HF patients are prescribed the same medications. Still, the current ‘one size fits all’ approach to patients with symptomatic HF with reduced ejection fraction has been extremely successful, and the introduction of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and aldosterone antagonists has resulted in a …

Galectin-3 predicts response to statin therapy in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)

To investigate whether plasma galectin-3, a mediator of fibrogenesis, can identify patients with chronic heart failure (HF) for whom statins are effective. Patients with ischaemic systolic HF enrolled in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) were randomly assigned to 10 mg/day of rosuvastatin or placebo. Galectin-3 was measured in plasma. The primary outcome was cardiovascular death, myocardial infarction, or stroke. Of 1492 patients, 411 had a primary event during a median follow-up of 32.8 months. There was an interaction between baseline galectin-3 and rosuvastatin on the primary endpoint (P-value for interaction = 0.036). Among patients with below the median plasma concentrations of galectin-3 (≤ 19.0 ng/mL), those assigned to rosuvastatin had a lower primary event rate [hazard ratio (HR) 0.65; 95% confidence interval (CI), 0.46-0.92; P= 0.014], lower total mortality (HR 0.70; 95% CI, 0.50-0.98; P= 0.038), and lower event rate of all-cause mortality and HF hospitalizations (HR 0.72; 95% CI, 0.54-0.98; P= 0.017) compared with placebo, but no benefit was observed in patients with higher levels of galectin-3. The combination of concurrently low concentrations of galectin-3 and N-terminal pro-B-type natriuretic peptide (<102.7 pmol/L) identified patients with a large benefit with rosuvastatin (HR 0.33; 95% CI, 0.16-0.67; P= 0.002). Patients with systolic HF of ischaemic aetiology who have galectin-3 values <19.0 ng/mL may benefit from rosuvastatin treatment. However, the data from this post hoc analysis should be interpreted with caution since the overall results of the CORONA study did not show a significant effect on the primary endpoint.

Considering the changing landscape of heart failure care

British Journal of Cardiac NursingVol. 7, No. 4 Meeting ReportConsidering the changing landscape of heart failure careJayne Masters, Suzy Hughes, Jane ButlerJayne MastersSearch for more papers by this author, Suzy HughesSearch for more papers by this author, Jane ButlerSearch for more papers by this authorJayne Masters; Suzy Hughes; Jane ButlerPublished Online:27 Sep 2013https://doi.org/10.12968/bjca.2012.7.4.194AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article References Anker S, Colet J, Filipatos M et al. for the FAIR-HF trial investigators (2009) Ferric Carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 361: 2436–2436 Crossref, Google ScholarHjalmarson A (2007) Controlled Rosuvastatin multinational trial in heart failure (CORONA) – results of an outcomes trial in patients with ischaemic heart disease and heart failure. American heart association 2007. Scientific session; November 5 2007; Orlando Fl Late breaking trials Google ScholarNational Institute for Cardiovascular Outcomes Research (2011) National Heart Failure Audit April 2010–March 2011. http://www.ucl.ac.uk/nicor/audits/heartfailure/additionalfiles/pdfs/annualre-ports/annual11.pdf (accessed 23 March 2012) Google ScholarTavazzi L, Maggioni AP, Machioli R et al. for the Gissi -HF trial investigators (2008) Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised double blind, placebo controlled trial. Lancet 372: 1231–1231 Crossref, Google ScholarWyse DG, Waldo AL, DiMarco JP et al. (2002) A comparison of rate control and rhythm control in patients with atrial fibrillation. The atrial fibrillation follow up investigation of rhythm management (AFFIRM) investigators. N Engl J Med 347: 1825–1825 Crossref, Google Scholar FiguresReferencesRelatedDetails 1 April 2012Volume 7Issue 4ISSN (online): 2052-2207 Metrics History Published online 27 September 2013 Published in print 1 April 2012 Information© MA Healthcare LimitedPDF download

Changes in Galectin-3 Levels over Time Predict Mortality and Morbidity in Chronic HF

Background: Elevated circulating levels of galectin-3, a protein implicated in myocardial fibrosis and remodeling, are associated with significantly increased risk of morbidity and mortality among chronic heart failure (HF) subjects. The clinical utility of serial measurements of galectin-3, however, has not been reported. Methods: Galectin-3 was measured at baseline and at 3 months in a study comprising 1,329 subjects of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA), and at baseline and 6 months in 324 subjects of the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH). An assay recently cleared by the U.S. Food and Drug Administration was used to measure galectin-3, and the indicated threshold value of 17.8 ng/mL was adopted to categorize subjects into 4 categories: subjects whose galectin-3 values remained either below or above 17.8 ng/mL, and subjects whose galectin-3 levels either increased or decreased between baseline and the second sampling time point. Results: Categorical changes in galectin-3 were observed in 17.3% of subjects from CORONA over 3 months, and 23.5% of subjects from COACH over 6 months. For the composite endpoint of total mortality and HF hospitalization, the outcome of subjects with a low baseline galectin-3 level that increased over time was significantly worse than that of subjects that maintained a low level (Cox hazard ratio (HR) in CORONA, 1.60 (95% CI: 1.152.22), p50.005; HR in COACH, 2.46 (95% CI: 1.05-5.73, p50.037)). Similarly, subjects with a high baseline level that decreased over time exhibited significantly fewer endpoints than subjects that remained high over time (HR in CORONA, 0.68 (95% CI: 0.49-0.94), p50.020; HR in COACH, 0.48 (95% CI: 0.27-0.87), p50.015). Analyses of multiple secondary endpoints yielded comparable results. Conclusions: In two large cohorts of chronic HF subjects, serial measurements of galectin-3 concentration are shown to provide important and significant prognostic value for morbidity and mortality risk assessment. 295

Exploring new indications for statins beyond atherosclerosis: Successes and setbacks

Statins have been shown to reduce cardiovascular events across a broad spectrum of patients at risk, irrespective of baseline LDL-cholesterol levels. In a meta-analysis of 14 statin trials involving more than 90,000 participants, statin therapy reduced the 5-year incidence of cardiovascular events by about 20% for each mmol/L of LDL-cholesterol reduction. The results of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study suggest that the degree of reduction in Japanese subjects may be greater than this for the same degree of LDL-cholesterol reduction. Given the success of statins in preventing cardiovascular events, it is not surprising that they have been tested in a variety of related conditions, three of which are discussed in this article. Heart failure is characterized by inflammation, endothelial dysfunction and neurohumeral activation, conditions that are ameliorated by statin therapy. The Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) showed no significant benefit of rosuvastatin upon the primary endpoint, cardiovascular death, myocardial infarction and stroke. However, subgroups identified by the biomarkers plasma amino-terminal pro-brain natriuretic and C-reactive protein showed a reduction in events. Aortic stenosis and atherosclerosis share common risk factors, including hypertension and hypercholesterolemia. Although non-randomized cohort studies have suggested that statins slow the progression of aortic stenosis, this was not shown in either of the two randomized placebo-controlled trials testing this hypothesis. Similarly, Alzheimer's disease shares many risk factors with atherosclerosis, and several observational studies have reported a lower risk of developing this condition in patients taking statins. However, two recently completed clinical trials indicate that neither atorvastatin nor simvastatin slow the progression of early Alzheimer's disease. In conclusion, although statins are effective, established therapy for the prevention of vascular events in patients at risk, they have as yet not proven to be successful for these newer indications.