Eileen O’Meara

Baseline Characteristics of Patients in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial

Background—Treatment of Preserved Cardiac Function with an Aldosterone Antagonist (TOPCAT) is an ongoing randomized controlled trial of spironolactone versus placebo for heart failure with preserved ejection fraction (HFpEF). We sought to describe the baseline clinical characteristics of subjects enrolled in TOPCAT relative to other contemporary observational studies and randomized clinical trials of HFpEF. Methods and Results—Between August 2006 and January 2012, 3445 patients with symptomatic HFpEF from 270 sites in 6 countries were enrolled in TOPCAT. At the baseline study visit, all subjects provided a detailed medical history and underwent physical examination, electrocardiography, quality of life, and laboratory assessment. Key parameters were compared with other large, contemporary HFpEF studies. The mean age was 68.6±9.6 years with a slight female predominance (52%); mean body mass index was 32 kg/m2; and comorbidities were common. History of hypertension (91% prevalence in TOPCAT) exceeded all other major HFpEF clinical trials. However, baseline blood pressure was well controlled (129/76 mm Hg; systolic blood pressure 7–16 mm Hg lower than other similar trials). Other common comorbidities included coronary artery disease (57%), atrial fibrillation (35%), chronic kidney disease (38%) and diabetes mellitus (32%). Self-reported activity levels were low, quality of life scores were comparable with those reported for patients with end-stage renal disease, and the prevalence of moderate or greater depression was 27%. Conclusions—TOPCAT subjects share many common characteristics with contemporary HFpEF cohorts. Low activity level, significantly decreased quality of life, and depression were common at baseline in TOPCAT, underscoring the continued unmet need for evidence-based treatment strategies in HFpEF. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

The 2010 Canadian Cardiovascular Society guidelines for the diagnosis and management of heart failure update: Heart failure in ethnic minority populations, heart failure and pregnancy, disease management, and quality improvement/assurance programs

Since 2006, the Canadian Cardiovascular Society heart failure (HF) guidelines have published annual focused updates for cardiovascular care providers. The 2010 Canadian Cardiovascular Society HF guidelines update focuses on an increasing issue in the western world - HF in ethnic minorities - and in an uncommon but important setting - the pregnant patient. Additionally, due to increasing attention recently given to the assessment of how care is delivered and measured, two critically important topics - disease management programs in HF and quality assurance - have been included. Both of these topics were written from a clinical perspective. It is hoped that the present update will become a useful tool for health care providers and planners in the ongoing evolution of care for HF patients in Canada.

Spironolactone Metabolites in TOPCAT — New Insights into Regional Variation

In a subgroup of TOPCAT participants assigned to spironolactone, the spironolactone metabolite canrenone was measured to assess adherence. Canrenone levels were undetectable in 30% of participants from Russia, as compared with only 3% from the United States and Canada.

The Canadian Cardiovascular Society Heart Failure Companion: Bridging Guidelines to Your Practice

The Canadian Cardiovascular Society Heart Failure (HF) Guidelines Program has generated annual HF updates, including formal recommendations and supporting Practical Tips since 2006. Many clinicians indicate they routinely use the Canadian Cardiovascular Society HF Guidelines in their daily practice. However, many questions surrounding the actual implementation of the Guidelines into their daily practice remain. A consensus-based approach was used, including feedback from the Primary and Secondary HF Panels. This companion is intended to answer several key questions brought forth by HF practitioners such as appropriate timelines for initial assessments and subsequent reassessments of patients, the order in which medications should be added, how newer medications should be included in treatment algorithms, and when left ventricular function should be reassessed. A new treatment algorithm for HF with reduced ejection fraction is included. Several other practical issues are addressed such as an approach to management of hyperkalemia/hypokalemia, treatment of gout, when medications can be stopped, and whether a target blood pressure or heart rate is suggested. Finally, elements and teaching of self-care are described. This tool will hopefully function to allow better integration of the HF Guidelines into clinical practice.

Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project I-A: study protocol for a randomized controlled trial

BackgroundIschemic heart disease (IHD) is the most common cause of heart failure (HF); however, the role of revascularization in these patients is still unclear. Consensus on proper use of cardiac imaging to help determine which candidates should be considered for revascularization has been hindered by the absence of clinical studies that objectively and prospectively compare the prognostic information of each test obtained using both standard and advanced imaging.Methods/DesignThis paper describes the design and methods to be used in the Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) multi-center trial. The primary objective is to compare the effect of HF imaging strategies on the composite clinical endpoint of cardiac death, myocardial infarction (MI), cardiac arrest and re-hospitalization for cardiac causes.In AIMI-HF, patients with HF of ischemic etiology (n = 1,261) will follow HF imaging strategy algorithms according to the question(s) asked by the physicians (for example, Is there ischemia and/or viability?), in agreement with local practices. Patients will be randomized to either standard (SPECT, Single photon emission computed tomography) imaging modalities for ischemia and/or viability or advanced imaging modalities: cardiac magnetic resonance imaging (CMR) or positron emission tomography (PET). In addition, eligible and consenting patients who could not be randomized, but were allocated to standard or advanced imaging based on clinical decisions, will be included in a registry.DiscussionAIMI-HF will be the largest randomized trial evaluating the role of standard and advanced imaging modalities in the management of ischemic cardiomyopathy and heart failure. This trial will complement the results of the Surgical Treatment for Ischemic Heart Failure (STICH) viability substudy and the PET and Recovery Following Revascularization (PARR-2) trial. The results will provide policy makers with data to support (or not) further investment in and wider dissemination of alternative ‘advanced’ imaging technologies.Trial registrationNCT01288560

Heart Failure With Anemia Novel Findings on the Roles of Renal Disease, Interleukins, and Specific Left Ventricular Remodeling Processes

Background— Anemia is a highly prevalent and strong independent prognostic marker in heart failure (HF), yet this association is not completely understood. Whether anemia is simply a marker of disease severity and concomitant chronic kidney disease or represents the activation of other detrimental pathways remains uncertain. We sought to determine which pathophysiological pathways are exacerbated in patients with HF, reduced ejection fraction (HFrEF) and anemia in comparison with those without anemia. Methods and Results— In a prospective study involving 151 patients, selected biomarkers were analyzed, each representing proposed contributive mechanisms in the pathophysiology of anemia in HF. We compared clinical, echocardiographic, and circulating biomarkers profiles among patients with HFrEF and anemia (group 1), HFrEF without anemia (group 2), and chronic kidney disease with preserved EF, without established HF (chronic kidney disease control group 3). We demonstrate here that many processes other than those related to chronic kidney disease are involved in the anemia–HF relationship. These are linked to the pathophysiological mechanisms pertaining to left ventricular systolic dysfunction and remodeling, systemic inflammation and volume overload. We found that levels of interleukin-6 and interleukin-10, specific markers of cardiac remodeling (procollagen type III N-terminal peptide, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase 1, left atrial volume), myocardial stretch (NT-proBNP [N-terminal probrain natriuretic peptide]), and myocyte death (troponin T) are related to anemia in HFrEF. Conclusions— Anemia is strongly associated not only with markers of more advanced and active heart disease but also with the level of renal dysfunction in HFrEF. Increased myocardial remodeling, inflammation, and volume overload are the hallmarks of patients with anemia and HF. Clinical Trial Registration— URL: . Unique identifier: [NCT00834691][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00834691&atom=%2Fcirchf%2F7%2F5%2F773.atomBackground—Anemia is a highly prevalent and strong independent prognostic marker in heart failure (HF), yet this association is not completely understood. Whether anemia is simply a marker of disease severity and concomitant chronic kidney disease or represents the activation of other detrimental pathways remains uncertain. We sought to determine which pathophysiological pathways are exacerbated in patients with HF, reduced ejection fraction (HFrEF) and anemia in comparison with those without anemia. Methods and Results—In a prospective study involving 151 patients, selected biomarkers were analyzed, each representing proposed contributive mechanisms in the pathophysiology of anemia in HF. We compared clinical, echocardiographic, and circulating biomarkers profiles among patients with HFrEF and anemia (group 1), HFrEF without anemia (group 2), and chronic kidney disease with preserved EF, without established HF (chronic kidney disease control group 3). We demonstrate here that many processes other than those related to chronic kidney disease are involved in the anemia–HF relationship. These are linked to the pathophysiological mechanisms pertaining to left ventricular systolic dysfunction and remodeling, systemic inflammation and volume overload. We found that levels of interleukin-6 and interleukin-10, specific markers of cardiac remodeling (procollagen type III N-terminal peptide, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase 1, left atrial volume), myocardial stretch (NT-proBNP [N-terminal probrain natriuretic peptide]), and myocyte death (troponin T) are related to anemia in HFrEF. Conclusions—Anemia is strongly associated not only with markers of more advanced and active heart disease but also with the level of renal dysfunction in HFrEF. Increased myocardial remodeling, inflammation, and volume overload are the hallmarks of patients with anemia and HF. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00834691.

Circulating Biomarkers in Patients with Heart Failure and Preserved Ejection Fraction

Patients with heart failure with preserved ejection fraction (HF-PEF) comprise a growing proportion of the overall HF burden. The pathophysiology of HF-PEF is complex, and relates to the interplay between cardiac risk factors (notably diabetes/insulin resistance, hypertension), systemic inflammation, and comorbid medical illness (e.g. chronic kidney disease) that conspire to promote endothelial dysfunction, ventricular-vascular stiffening, and diastolic dysfunction. Efficient diagnosis and optimal therapy remain challenging in this population. Imaging, electrocardiographic, and circulating biomarkers, as well as pharmacogenetics, may help to facilitate HF diagnosis, stratify risk, and individualize therapy. In this review, we focus on established and emerging circulating biomarkers in HF-PE, including circulating biomarkers of myocyte stress, myocyte injury, renal function, systemic inflammation, and fibrosis. Such markers have contributed to better understanding of the pathophysiologic mechanisms relevant to HF-PEF, and may eventually help to facilitate more effective and personalized management of this syndrome.

Anxiety Sensitivity Moderates Prognostic Importance of Rhythm-Control Versus Rate-Control Strategies in Patients With Atrial Fibrillation and Congestive Heart Failure Insights From the Atrial Fibrillation and Congestive Heart Failure Trial

Background— Patients with high anxiety sensitivity (AS) become extremely anxious with heart rate increases, palpitations, and symptoms of psychological arousal. AS predicts panic attacks. In atrial fibrillation (AF), AS correlates with symptom preoccupation and reduced quality of life. We assessed whether AS is associated with outcomes of rhythm-control versus rate-control in congestive heart failure (CHF) patients with AF. Methods and Results— Before random assignment, 933 participants (172 women) in the Atrial Fibrillation and Congestive Heart Failure Trial completed the Anxiety Sensitivity Inventory (ASI). Cox proportional hazards models showed no main effects of treatment (P=0.61) or AS (P=0.72) for time to cardiovascular death, but these factors interacted significantly (P=0.020). High AS patients (upper quartile, ASI ≥33) randomly assigned to rhythm-control had significantly lower cardiovascular mortality than those receiving rate-control (hazard ratio, 0.54; 95% confidence interval, 0.32–0.93; P=0.022). With lower ASI scores (<33), treatments did not differ (hazard ratio, 1.12; 95% confidence interval, 0.83–1.51; P=0.46). The interaction between treatment and dichotomized ASI scores remained significant (P=0.009) after adjustment for covariates including age, sex, hypertension, diabetes, creatinine, ejection fraction, time since first diagnosis of AF, New York Heart Association functional class, depression symptoms, marital status, and baseline &bgr;-blockers, angiotensin-converting enzyme inhibitors, oral anticoagulants, and implantable cardioverter-defibrillators. Conclusions— Atrial fibrillation and congestive heart failure patients with high AS had better long-term prognosis with rhythm- than rate-control. If replicated, AS should be considered in treatment selection. Research is also needed concerning mechanisms and possible joint AS-AF treatments. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT88597077.

Changes in Cardiopulmonary Reserve and Peripheral Arterial Function Concomitantly with Subclinical Inflammation and Oxidative Stress in Patients with Heart Failure with Preserved Ejection Fraction

Background. Changes in cardiopulmonary reserve and biomarkers related to wall stress, inflammation, and oxidative stress concomitantly with the evaluation of peripheral arterial blood flow have not been investigated in patients with heart failure with preserved ejection fraction (HFpEF) compared with healthy subjects (CTL). Methods and Results. Eighteen HFpEF patients and 14 CTL were recruited. Plasma levels of inflammatory and oxidative stress biomarkers were measured at rest. Brain natriuretic peptide (BNP) was measured at rest and peak exercise. Cardiopulmonary reserve was assessed using an exercise protocol with gas exchange analyses. Peripheral arterial blood flow was determined by strain gauge plethysmography. Peak VO2 (12.0 ± 0.4 versus 19.1 ± 1.1 mL/min/kg, P < 0.001) and oxygen uptake efficiency slope (1.55 ± 0.12 versus 2.06 ± 0.14, P < 0.05) were significantly decreased in HFpEF patients compared with CTL. BNP at rest and following stress, C-reactive-protein, interleukin-6, and TBARS were significantly elevated in HFpEF. Both basal and posthyperemic arterial blood flow were not significantly different between the HFpEF patients and CTL. Conclusions. HFpEF exhibits a severe reduction in cardiopulmonary reserve and oxygen uptake efficiency concomitantly with an elevation in a broad spectrum of biomarkers confirming an inflammatory and prooxidative status in patients with HFpEF.

Mineralocorticoid Receptor Antagonists and Cardiovascular Mortality in Patients With Atrial Fibrillation and Left Ventricular Dysfunction Insights From the Atrial Fibrillation and Congestive Heart Failure Trial

Background—Patients with heart failure (HF) and atrial fibrillation (AF) may differ from the larger HF population with respect to comorbidities, including renal impairment and overall prognosis. Associated cardiorenal interactions may mitigate the effects of pharmacological agents. Our primary objective was to assess the impact of mineralocorticoid receptor antagonists on cardiovascular mortality in patients with AF and HF enrolled in the Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial. Methods and Results—All 1376 patients randomized in the AF-CHF trial were included. The median baseline creatinine was 105.2 (Q1 88.4, Q3 125.0) &mgr;mol/L, and the median estimated glomerular filtration rate was 62.3 (Q1 49.0, Q3 77.2) mL/min per 1.73 m2. The renal function was moderately or severely impaired (ie, estimated glomerular filtration rate <60 mL/min per 1.73 m2) in 46.5% of patients. In multivariable analyses, increased creatinine was associated with worsening HF but not mortality. Mineralocorticoid receptor antagonists were prescribed in 44.8% and were independently associated with a 1.4-fold increase in total mortality (hazard ratio, 1.4; 95% CI [1.1–1.8]; P=0.005) and a 1.4-fold increase in cardiovascular mortality (hazard ratio, 1.4; 95% CI [1.1–1.9]; P=0.009). This was driven by an increased incidence of sudden cardiac death (hazard ratio, 2.0; 95% CI [1.3, 3.0]; P=0.001). Conclusions—Renal dysfunction was highly prevalent in patients with AF and HF. Mineralocorticoid receptor antagonists were independently associated with an increased incidence of cardiovascular deaths, predominantly of presumed arrhythmic cause. Although these provocative findings merit prospective validation, they underscore the importance of careful monitoring of renal function and electrolytes in patients with AF and HF receiving mineralocorticoid receptor antagonists. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00597077.