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Aims: Guidelines for the management of heart failure (HF) are evolving, and increasing emphasis is placed on patient-centred care. As part of the REWOLUTION HF (REal WOrLd EdUcaTION in HF) programme, we conducted two international surveys aimed at assessing healthcare professionals' (HCPs) educational needs and patients' perspectives on the care of HF., Methods and Results: Anonymous online questionnaires co-developed by HF experts and patients assessed HCPs' educational needs (520 respondents, mostly cardiologists, in 67 countries) and patients' perceptions on HF impact and management (98 respondents in 18 countries). Among HCPs, 62.7% prioritized rapid initiation of all guideline-mandated medications over up-titration of some medications, and 87.7% always or frequently discussed treatment goals with patients. There was good agreement between HCPs and patients on key treatment goals, except for a greater emphasis on reducing hospitalizations among HCPs. The most frequently cited barriers to the provision of guideline-recommended pharmacological therapy were treatment side effects/intolerance, complex treatment regimens, low blood pressure, cost/reimbursement issues, and low estimated glomerular filtration rate. Most patients (81.6%) reported no difficulties taking medications as prescribed, although 21.4% felt they were taking too many pills. Patients wanted more information about HF and its consequences, prognosis, and treatments (70.4%, 74.5% and 76.6%, respectively). Cardiologists were the preferred source of information about HF, followed by general practitioners and HF nurses., Conclusions: These surveys provide valuable insights into HCPs' needs about personalized care for patients with HF, as well as patients' perceptions, expectations and preferences. These findings will be helpful to develop patient-centred, needs-driven quality improvement programmes., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Heart failure (HF) is a critical complication in elderly patients with atrial fibrillation (AF) and diabetes mellitus (DM). Recent preclinical studies suggested that non-vitamin K antagonist oral anticoagulants (NOACs) can potentially suppress the progression of cardiac fibrosis and ischemic cardiomyopathy. Whether different oral anticoagulants influence the risk of HF in older adults with AF and DM is unknown. This study aimed to evaluate the risk of HF in elderly patients with AF and DM who were administered NOACs or warfarin., Methods: A nationwide retrospective cohort study was conducted based on claims data from the entire Taiwanese population. Target trial emulation design was applied to strengthen causal inference using observational data. Patients aged  ≥ 65 years with AF and DM on NOAC or warfarin treatment between 2012 and 2019 were included and followed up until 2020. The primary outcome was newly diagnosed HF. Propensity score-based fine stratification weightings were used to balance patient characteristics between NOAC and warfarin groups. Hazard ratios (HRs) were estimated using Cox proportional hazard models., Results: The study included a total of 24,835 individuals (19,710 NOAC and 5,125 warfarin users). Patients taking NOACs had a significantly lower risk of HF than those taking warfarin (HR = 0.80, 95% CI 0.74-0.86, p < 0.001). Subgroup analyses for individual NOACs suggested that dabigatran (HR = 0.86, 95% CI 0.80-0.93, p < 0.001), rivaroxaban (HR = 0.80, 95% CI 0.74-0.86, p < 0.001), apixaban (HR = 0.78, 95% CI 0.68-0.90, p < 0.001), and edoxaban (HR = 0.72, 95% CI 0.60-0.86, p < 0.001) were associated with lower risks of HF than warfarin. The findings were consistent regardless of age and sex subgroups and were more prominent in those with high medication possession ratios. Several sensitivity analyses further supported the robustness of our findings., Conclusions: This nationwide cohort study demonstrated that elderly patients with AF and DM taking NOACs had a lower risk of incident HF than those taking warfarin. Our findings suggested that NOACs may be the preferred oral anticoagulant treatment when considering the prevention of heart failure in this vulnerable population. Future research is warranted to elucidate causation and investigate the underlying mechanisms., (© 2023. The Author(s).)

Objective: Heart failure (HF) often develops in patients with diabetes and is recognized for its role in increased cardiovascular morbidity and mortality in this population. Most existing models predict risk in patients with prevalent rather than incident diabetes and fail to account for sex differences in HF risk factors. We derived sex-specific models in Ontario, Canada to predict HF at diabetes onset and externally validated these models in the U.K., Research Design and Methods: Retrospective cohort study using international population-based data. Our derivation cohort comprised all Ontario residents aged ≥18 years who were diagnosed with diabetes between 2009 and 2018. Our validation cohort comprised U.K. patients aged ≥35 years who were diagnosed with diabetes between 2007 and 2017. Primary outcome was incident HF. Sex-stratified multivariable Fine and Gray subdistribution hazard models were constructed, with death as a competing event., Results: A total of 348,027 Ontarians (45% women) and 54,483 U.K. residents (45% women) were included. At 1, 5, and 9 years, respectively, in the external validation cohort, the C-statistics were 0.81 (95% CI 0.79-0.84), 0.79 (0.77-0.80), and 0.78 (0.76-0.79) for the female-specific model; and 0.78 (0.75-0.80), 0.77 (0.76-0.79), and 0.77 (0.75-0.79) for the male-specific model. The models were well-calibrated. Age, rurality, hypertension duration, hemoglobin, HbA1c, and cardiovascular diseases were common predictors in both sexes. Additionally, mood disorder and alcoholism (heavy drinker) were female-specific predictors, while income and liver disease were male-specific predictors., Conclusions: Our findings highlight the importance of developing sex-specific models and represent an important step toward personalized lifestyle and pharmacologic prevention of future HF development., (© 2022 by the American Diabetes Association.)

Objectives: To examine the temporal trends in mortality and heart failure (HF) hospitalisation in ambulatory patients following a new diagnosis of HF., Design: Retrospective cohort study SETTING: Outpatient PARTICIPANTS: Ontario residents who were diagnosed with HF in an outpatient setting between 1994 and 2013., Primary and Secondary Outcome Measures: The primary outcome was all-cause mortality within 1 year of diagnosis and the secondary outcome was HF hospitalisation within 1 year. Risks of mortality and hospitalisation were calculated using the Kaplan-Meier method and the relative hazard of death was assessed using multivariable Cox proportional hazard models., Results: A total of 352 329 patients were studied (50% female). During the study period, there was a greater decline in age standardised 1-year mortality rates (AMR) in men (33%) than in women (19%). Specifically, female AMR at 1 year was 10.4% (95% CI 9.1% to 12.0%) in 1994 and 8.5% (95% CI 7.5% to 9.5%) in 2013, and male AMR at 1 year was 12.3% (95% CI 11.1% to 13.7%) in 1994 and 8.3% (95% CI 7.5% to 9.1%) in 2013. Conversely, age standardised HF hospitalisation rates declined in men (11.4% (95% CI 10.1% to 12.9%) in 1994 and 9.1% (95% CI 8.2% to 10.1%) in 2013) but remained unchanged in women (9.7% (95% CI 8.3% to 11.3%) in 1994 and 9.8% (95% CI 8.6% to 11.0%) in 2013)., Conclusion: Among patients with HF over a 20-year period, there was a greater improvement in the prognosis of men compared with women. Further research should focus on the determinants of this disparity and ways to reduce this gap in outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This state-of-the-art review aims to provide an up-to-date look at breakthrough omic technologies that are helping to unravel heart failure (HF) disease mechanisms and heterogeneity. Genomics, transcriptomics, proteomics, and metabolomics in HF are reviewed in depth. In addition, there is a thorough, expert discussion regarding the value of omics in identifying novel disease pathways, advancing understanding of disease mechanisms, differentiating HF phenotypes, yielding biomarkers for diagnosis or prognosis, or identifying new therapeutic targets in HF. The combination of multiple omics technologies may create a more comprehensive picture of the factors and physiology involved in HF than achieved by either one alone and provides a rich resource for predictive phenotype modelling. However, the successful translation of omics tools as solutions to clinical HF requires that the observations are robust and reproducible and can be validated across multiple independent populations to ensure confidence in clinical decision-making., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Previous studies have identified ethnic differences in outcomes after episodes of acute heart failure in natives of Asia as compared to those of Europe. Whether these ethnic differences in outcomes would still exist, years after migration to a different geographical and cultural setting remain unclear. We investigated the one-year mortality after an episode of acute heart failure admission in Ontario residents of South Asian and Chinese descent as compared to the General Population., Methods: We conducted a population-based, retrospective cohort study of adult Ontarions who were hospitalized for AHF between April 1, 2010 and March 31, 2016. Ethnicity was categorized using validated surname-based algorithms. The primary outcome was all-cause one-year mortality. Mortality rates were calculated using the Kaplan-Meier method. The relative hazard of death was assessed using a multivariable Cox proportional hazard model., Results: Of 82,125 patients, 1287 (1.6%) were Chinese, 1662 (2.0%) were South Asians, and the remaining 79,176 (96.4%) were of the General Population. The risk of mortality was markedly lower amongst South Asians (adjusted HR 0.81, 95% CI [0.73-0.89]) relative to the General Population. There was no statistically significant difference in the risk of mortality between Chinese and the General Population (adjusted HR 1.00 [0.91-1.10]). In addition, guideline-directed medical therapies were associated with similar survival benefit in patients of all three ethnic origins., Conclusions: We found a lower risk of one-year mortality after acute heart failure hospitalization amongst South Asians compared to Chinese and the General Population, and similar benefit of medical therapy in all three groups. Further studies are needed to explore the etiologies of these ethnic disparities to truly improve outcomes at the population level., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Several known traditional cardiovascular risk factors contribute to the development of heart failure (HF); however, whether ethnicity is also an important predictor is not well established. We determined the incidence of hospitalization for HF among ethnic groups in Ontario, Canada, and examined differences in risk factor prevalence that may contribute to disparities in HF hospitalization incidence between groups., Methods and Results: We conducted a retrospective observational study from 2008 to 2012 with the use of a linked cohort derived from population-based health administrative, clinical, and survey datasets. We followed 895,823 recent immigrants from 8 ethnic groups and 5.3 million long-term residents aged 40-105 years for incident HF hospitalization. Sex-stratified age-standardized HF incidence was lower among all immigrant groups than long-term residents. Among immigrants, Black men and West Asian women had the highest incidence of hospitalizations for HF (1.19 and 1.60 per 1000 person-years, respectively), and East Asians of both sexes had the lowest incidence. After adjusting for sociodemographic characteristics, comorbidities, and other risk factors, the association between ethnicity and HF hospitalization risk remained significant., Conclusions: HF hospitalization incidence varies widely among ethnic immigrant groups, highlighting the importance of ethnicity as a potential independent risk factor for HF development., (Copyright © 2019. Published by Elsevier Inc.)

Background: Geographic factors may influence cardiovascular disease outcomes in Canada. Circulatory diseases are a major reason for higher population mortality rates in Northern Ontario, but it is unknown if hospitalized patients with cardiovascular disease experience differential outcomes compared with those in the South., Methods: We examined 30-day and 1-year mortality and readmissions for patients hospitalized with acute myocardial infarction (AMI), heart failure (HF), atrial fibrillation (AF), or stroke in Northern compared with Southern Ontario, using the Canadian Institute for Health Information Discharge Abstract Database (2005-2016). Northern patients were defined as those residing and hospitalized in the Northwest or Northeast Local Health Integration Network regions. We used multiple Cox proportional hazards regression analysis for time-to-first event and Prentice-Williams-Peterson method to evaluate repeat and multiply admitted patients., Results: A total of 47,745 Northern and 465,353 Southern patients hospitalized with AMI (n = 182,158), HF (n = 130,770), AF (n = 72,326), or stroke (n = 127,844) were studied. Rates of first readmission were higher among Northern patients for AMI (adjusted hazard ratio [HR], 1.32), HF (HR, 1.16), AF (HR, 1.21), and stroke (HR, 1.27) compared with Southern patients (all P < 0.001). Repeat readmission rates among Northern patients for AMI (HR, 1.23), HF (HR, 1.13), AF (HR, 1.18), and stroke (HR, 1.22) were also increased (all P < 0.001 vs Southern). Thirty-day mortality did not differ significantly between Northern and Southern patients., Conclusions: Readmissions were increased in those residing and hospitalized in the North. To reduce readmissions in the North, the quality of postacute transitional care should be examined further., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure (HF) with reduced ejection fraction (rEF) is a widely regarded prognosticator after coronary artery bypass grafting. HF with preserved ejection fraction (pEF) accounts for up to half of all HF cases and is associated with considerable morbidity and mortality in hospitalized cohorts. However, HFpEF outcomes have not been elucidated in cardiac surgical patients. We investigated the prevalence and outcomes of HFpEF and HFrEF in women and men following coronary artery bypass grafting., Methods and Results: We conducted a retrospective cohort study in Ontario, Canada, between October 1, 2008, and March 31, 2015, using Cardiac Care Network and Canadian Institute of Health Information data. HF is captured through a validated population-based database of all Ontarians with physician-diagnosed HF. We defined pEF as ejection fraction ≥50% and rEF as ejection fraction <50%. The primary outcome was all-cause mortality. Analyses were stratified by sex. Mortality rates were calculated using Kaplan-Meier method. The relative hazard of death was assessed using multivariable Cox proportional hazard models. Of 40 083 patients (20.6% women), 55.5% had pEF without HF, 25.7% had rEF without HF, 6.9% had HFpEF, and 12.0% had HFrEF. Age-standardized HFpEF mortality rates at 4±2 years of follow-up were similar in women and men. HFrEF standardized HFpEF mortality rates were higher in women than men., Conclusions: We found a higher prevalence and poorer prognosis of HFpEF in women. A history of HF was a more important prognosticator than ejection fraction. Preoperative screening and extended postoperative follow-up should be focused on women and men with HF rather than on rEF alone., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Increased N-terminal pro b-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) can identify patients with heart failure (HF) who are at increased risk of cardiac events. The relationship of these biomarkers to the extent of hibernating myocardium and scar has not been previously characterized in patients with ischemic left ventricular dysfunction and HF., Methods: Patients with ischemic HF meeting recruitment criteria and undergoing perfusion and fluorodeoxyglucose-positron emission tomography to define myocardial hibernation and scar were included in the study. A total of 39 patients (mean age 67 ± 8 years) with New York Heart Association class II-IV HF and ischemic cardiomyopathy (ejection fraction [EF], 27.9% ± 8.5%) were enrolled in the study., Results: Serum NT-proBNP and hs-cTnT levels were elevated in patients with ≥ 10% hibernating myocardium compared with those with < 10% (NT-pro-BNP, 7419.10 ± 7169.5 pg/mL vs 2894.6 ± 2967.4 pg/mL; hs-cTnT, 789.3 ± 1835.3 pg/mL vs 44.8 ± 78.9 pg/mL; P < 0.05). The overall receiver operating characteristic under the curve value for NT-proBNP and hs-cTnT to predict hibernating myocardium was 0.76 and 0.78, respectively (P < 0.05). The NT-proBNP (P = 0.02) and hs-cTnT (P < 0.0001) levels also correlated with hibernation, particularly in patients with ≥ 10% scar, independent of EF, age, and estimated glomerular filtration rate. No differences were noted in biomarker levels for patients with vs those without ≥ 10% scar., Conclusions: NT-proBNP and hs-cTnT levels are elevated in patients with ischemic HF hibernation and are correlated with the degree of hibernation but not with the presence or extent of scar. Taken together, these data support the novel concept that NT-proBNP and hs-cTnT release in patients with ischemic HF reflects the presence and extent of hibernating myocardium., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Natriuretic peptides have led the way as a diagnostic and prognostic tool for the diagnosis and management of heart failure (HF). More recent evidence suggests that natriuretic peptides along with the next generation of biomarkers may provide added value to medical management, which could potentially lower risk of mortality and readmissions. The purpose of this scientific statement is to summarize the existing literature and to provide guidance for the utility of currently available biomarkers., Methods: The writing group used systematic literature reviews, published translational and clinical studies, clinical practice guidelines, and expert opinion/statements to summarize existing evidence and to identify areas of inadequacy requiring future research. The panel reviewed the most relevant adult medical literature excluding routine laboratory tests using MEDLINE, EMBASE, and Web of Science through December 2016. The document is organized and classified according to the American Heart Association to provide specific suggestions, considerations, or contemporary clinical practice recommendations., Results: A number of biomarkers associated with HF are well recognized, and measuring their concentrations in circulation can be a convenient and noninvasive approach to provide important information about disease severity and helps in the detection, diagnosis, prognosis, and management of HF. These include natriuretic peptides, soluble suppressor of tumorgenicity 2, highly sensitive troponin, galectin-3, midregional proadrenomedullin, cystatin-C, interleukin-6, procalcitonin, and others. There is a need to further evaluate existing and novel markers for guiding therapy and to summarize their data in a standardized format to improve communication among researchers and practitioners., Conclusions: HF is a complex syndrome involving diverse pathways and pathological processes that can manifest in circulation as biomarkers. A number of such biomarkers are now clinically available, and monitoring their concentrations in blood not only can provide the clinician information about the diagnosis and severity of HF but also can improve prognostication and treatment strategies., Competing Interests: The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest., (© 2017 American Heart Association, Inc.)

Background: There remains limited insight into the pathophysiology and therapeutic advances directed at improving prognosis for patients with heart failure with preserved ejection fraction (HFpEF). Recent studies have suggested a role for coronary microvascular dysfunction in HFpEF. Rb-82 cardiac positron emission tomography imaging is a noninvasive, quantitative approach to measuring myocardial flow reserve (MFR), a surrogate marker for coronary vascular health. The aim of this study was to determine whether abnormalities exist in MFR in patients with HFpEF without epicardial coronary artery disease., Methods and Results: A total of 376 patients with ejection fraction ≥50%, no known history of obstructive coronary artery disease, and a confirmed diagnosis of heart failure (n=78) were compared with patients with no evidence of heart failure (n=298), further stratified into those with (n=186) and without (n=112) hypertension. Global and regional left ventricular MFR was calculated as stress/rest myocardial blood flow using Rb-82 positron emission tomography. Patients with HFpEF were more likely to be older, female, and have comorbid hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, anemia, and renal dysfunction. HFpEF was associated with a significant reduction in global MFR (2.16±0.69 in HFpEF versus 2.54±0.80 in hypertensive controls; P<0.02 and 2.89±0.70 in normotensive controls; P<0.001). A diagnosis of HFpEF was associated with 2.62 times greater unadjusted odds of having low global MFR (defined as <2.0) and remained a significant predictor of reduced global MFR after adjusting for comorbidities., Conclusions: HFpEF, in the absence of known history for obstructive epicardial coronary artery disease, is associated with reduced MFR independent of other risk factors., (© 2016 American Heart Association, Inc.)

The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Update provides discussion on the management recommendations on 3 focused areas: (1) anemia; (2) biomarkers, especially natriuretic peptides; and (3) clinical trials that might change practice in the management of patients with heart failure. First, all patients with heart failure and anemia should be investigated for reversible causes of anemia. Second, patients with chronic stable heart failure should undergo natriuretic peptide testing. Third, considerations should be given to treat selected patients with heart failure and preserved systolic function with a mineralocorticoid receptor antagonist and to treat patients with heart failure and reduced ejection fraction with an angiotensin receptor/neprilysin inhibitor, when the drug is approved. As with updates in previous years, the topics were chosen in response to stakeholder feedback. The 2014 Update includes recommendations, values and preferences, and practical tips to assist the clinicians and health care workers to best manage patients with heart failure., (Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

The 2013 Canadian Cardiovascular Society Heart Failure Management Guidelines Update provides focused discussions on the management recommendations on 2 topics: (1) exercise and rehabilitation; and (2) surgical coronary revascularization in patients with heart failure. First, all patients with stable New York Heart Association class I-III symptoms should be considered for enrollment in a tailored exercise training program, to improve exercise tolerance and quality of life. Second, selected patients with suitable coronary anatomy should be considered for bypass graft surgery. As in previous updates, the topics were chosen in response to stakeholder feedback. The 2013 Update also includes recommendations, values and preferences, and practical tips to assist the clinicians and health care workers manage their patients with heart failure., (Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure (HF) is associated with a high burden of morbidity and mortality. Hospital discharge is an opportunity for identification of modifiable prognostic factors in the transition to chronic HF., Methods and Results: We examined the association of discharge heart rate with 30-day and 1-year mortality and hospitalization outcomes in a cohort of 9097 patients with HF discharged from hospital. Discharge heart rate was categorized into predefined groups: 40 to 60 (n=1333), 61 to 70 (n=2170), 71 to 80 (n=2631), 81 to 90 (n=1700), and >90 bpm (n=1263). There was a significant increase in all-cause 30-day mortality with adjusted odds ratios of 1.59 (95% confidence interval [CI], 1.18-2.14; P=0.003) for discharge heart rates 81 to 90 bpm and 1.56 (95% CI, 1.13-2.16; P=0.007) for heart rates>90 bpm when compared with the reference group (heart rates, 61-70 bpm). Cardiovascular death risk at 30 days was also higher with adjusted odds ratio 1.59 (discharge heart rates, 81-90 bpm; 95% CI, 1.09-2.33; P=0.017) and 1.65 (discharge heart rates, >90 bpm; 95% CI, 1.09-2.48; P=0.017). One-year all-cause mortality (adjusted odds ratio, 1.41; 95% CI, 1.16-1.72; P<0.001) and cardiovascular death (adjusted odds ratio, 1.47; 95% CI, 1.12-1.92; P=0.005) were higher with discharge heart rates>90 bpm when compared with the reference group (heart rates, 40-60 bpm). Readmissions for HF (adjusted hazard ratio, 1.26; 95% CI, 1.04-1.54; P=0.021) and cardiovascular disease (adjusted hazard ratio, 1.29; 95% CI, 1.08-1.54; P=0.004) within 30 days were also higher with discharge heart rates>90 bpm., Conclusions: Higher discharge heart rates were associated with greater risk of all-cause and cardiovascular mortality≤1-year follow-up and an elevated risk of 30-day readmission for HF and cardiovascular disease.

Angiotensin converting enzyme 2 (ACE2) is a negative regulator of the renin-angiotensin system (RAS), catalyzing the conversion of Angiotensin II to Angiotensin 1-7. Apelin is a second catalytic substrate for ACE2 and functions as an inotropic and cardioprotective peptide. While an antagonistic relationship between the RAS and apelin has been proposed, such functional interplay remains elusive. Here we found that ACE2 was downregulated in apelin-deficient mice. Pharmacological or genetic inhibition of angiotensin II type 1 receptor (AT1R) rescued the impaired contractility and hypertrophy of apelin mutant mice, which was accompanied by restored ACE2 levels. Importantly, treatment with angiotensin 1-7 rescued hypertrophy and heart dysfunctions of apelin-knockout mice. Moreover, apelin, via activation of its receptor, APJ, increased ACE2 promoter activity in vitro and upregulated ACE2 expression in failing hearts in vivo. Apelin treatment also increased cardiac contractility and ACE2 levels in AT1R-deficient mice. These data demonstrate that ACE2 couples the RAS to the apelin system, adding a conceptual framework for the apelin-ACE2-angiotensin 1-7 axis as a therapeutic target for cardiovascular diseases.

Despite therapeutic advances, patients with worsening heart failure (HF) requiring hospitalization have unacceptably high post-discharge mortality and re-admission rates soon after discharge. Evidence suggests a hypercoagulable state is present in patients with HF. Although thromboembolism as a direct consequence of HF is not frequently clinically recognized, it may contribute to mortality and morbidity. Additionally, many patients with HF have concomitant disorders conferring additional thrombotic risk, including atrial fibrillation (AF) and coronary artery disease (CAD). Acute coronary syndrome (ACS), a known consequence of coronary thrombosis, is a common precipitating factor for worsening HF. Coronary thrombosis may also cause sudden death in patients with HF and CAD. Because data are largely derived from observational studies or trials of modest size, guideline recommendations on anticoagulation for HF vary between organizations. The recently presented Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial of HF patients in sinus rhythm suggested anticoagulation reduces the risk of stroke, although rates of the combined primary endpoint (death, ischemic stroke, or intracerebral hemorrhage) were similar for acetylsalicylic acid and warfarin. Newer oral anticoagulants dabigatran, apixaban, and rivaroxaban have successfully completed trials for the prevention of stroke in patients with AF and have shown benefits in the subpopulation of patients with concomitant HF. Positive results of the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) trial of rivaroxaban in ACS are also encouraging. These data suggest there is a need to assess the potential role for these newer agents in the management of patients hospitalized for HF who continue to have a high post-discharge event rate despite available therapies.

In-depth proteomic analyses offer a systematic way to investigate protein alterations in disease and, as such, can be a powerful tool for the identification of novel biomarkers. Here, we analyzed proteomic data from a transgenic mouse model with cardiac-specific overexpression of activated calcineurin (CnA), which results in severe cardiac hypertrophy. We applied statistically filtering and false discovery rate correction methods to identify 52 proteins that were significantly different in the CnA hearts compared to controls. Subsequent informatic analysis consisted of comparison of these 52 CnA proteins to another proteomic dataset of heart failure, three available independent microarray datasets, and correlation of their expression with the human plasma and urine proteome. Following this filtering strategy, four proteins passed these selection criteria, including myosin heavy chain 7, insulin-like growth factor-binding protein 7, annexin A2, and desmin. We assessed expression levels of these proteins in mouse plasma by immunoblotting, and observed significantly different levels of expression between healthy and failing mice for all four proteins. We verified antibody cross-reactivity by examining human cardiac explant tissue by immunoblotting. Finally, we assessed protein levels in plasma samples obtained from four unaffected and four heart failure patients and demonstrated that all four proteins increased between twofold and 150-fold in heart failure. We conclude that MYH7, IGFBP7, ANXA2, and DESM are all excellent candidate plasma biomarkers of heart failure in mouse and human., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The 2012 Canadian Cardiovascular Society Heart Failure (HF) Guidelines Update provides management recommendations for acute and chronic HF. In 2006, the Canadian Cardiovascular Society HF Guidelines committee first published an overview of HF management. Since then, significant additions to and changes in many of these recommendations have become apparent. With this in mind and in response to stakeholder feedback, the Guidelines Committee in 2012 has updated the overview of both acute and chronic heart failure diagnosis and management. The 2012 Update also includes recommendations, values and preferences, and practical tips to assist the medical practitioner manage their patients with HF., (Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

This review provides the rationale for integrating genomic and protein biomarkers in the evolving diagnosis and management of dilated cardiomyopathy (DCM) and its causal pathway to heart failure (HF), with a larger objective to serve as a template for genomic and phenomic profiling of other cardiovascular disease. DCM is a major cause of HF and accounts for more than half of heart transplantation in adults and children worldwide. DCM may remain asymptomatic for years, but HF and/or arrhythmias, both late manifestations of the disease, ultimately cause significant morbidity and mortality. A significant proportion of DCM has a genetic etiology. DCM can also result from environmental injury such as infection, toxins, or catecholamine excess. While molecular genetic testing can identify those at risk for genetic DCM, epigenetic and sentinel phenomic staging can help to identify those at highest risk in need for intervention. Phenomic staging includes integrating clinical and imaging features, transcriptomics, higher order proteomics and metabolomics interactions, and epidemiological data. This principle can be applied in family members of patients with DCM, where genetic testing and clinical phenotyping are indicated. This will allow the design of specific interventions tailored to individuals sharing similar risks, to alter the natural history of DCM and obviate complications such as HF/arrhythmias., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The incidence and prevalence of heart failure have increased significantly over the past few decades. Available data suggest that patients with heart failure independent of the aetiology have viable but dysfunctional myocardium that is potentially salvageable. Although a great deal of research effort has focused on characterizing the molecular basis of heart failure, cardiac metabolism in this disorder remains an understudied discipline. It is known that many aspects of cardiomyocyte energetics are altered in heart failure. These include a shift from fatty acid to glucose as a preferred substrate and a decline in the levels of ATP. Despite these demonstrated changes, there are currently no approved drugs that target metabolic enzymes or proteins in heart failure. This is partly due to our limited knowledge of the mechanisms and pathways that regulate cardiac metabolism. Better characterization of these pathways may potentially lead to new therapies for heart failure. Targeting myocardial energetics in the viable and potentially salvageable tissue may be particularly effective in the treatment of heart failure. Here, we will review metabolic changes that occur in fatty acid and glucose metabolism and AMP-activated kinase in heart failure. We propose that cardiac energetics should be considered as a potential target for therapy in heart failure and more research should be done in this area.

Cellular FLICE-inhibitory protein (cFLIP) is a member of the tumour necrosis factor signalling pathway and a regulator of apoptosis, and it has a role in cardiac remodelling following myocardial infarction (MI) that remains largely uncharacterised. This study aimed to determine the function of cFLIP as a potential mediator of post-infarction cardiac remodelling. Our results show diminished cFLIP expression in failing human and murine post-infarction hearts. Genetically engineered cFLIP heterozygous (cFLIP+/-, HET) mice, cardiac-specific cFLIP-overexpressing transgenic (TG) mice and their respective wild-type (WT) and non-transgenic controls were subjected to MI by permanent ligation of their left anterior descending artery. Cardiac structure and function were assessed by echocardiography and pressure-volume loop analysis. Apoptosis, inflammation, angiogenesis, and fibrosis were evaluated in the myocardium. The HET mice showed exacerbated left ventricular (LV) contractile dysfunction, dilatation, and remodelling compared with WT mice 28 days after MI. Impaired LV function in the HET mice was associated with increases in infarct size, hypertrophy, apoptosis, inflammation, and interstitial fibrosis, and reduced capillary density. The TG mice displayed the opposite phenotype after MI. Moreover, adenovirus-mediated overexpression of cFLIP decreased LV dilatation and improved LV function and remodelling in both HET and WT mice. Further analysis of signalling events suggests that cFLIP promotes cardioprotection by interrupting JNK1/2 signalling and augmenting Akt signalling. In conclusion, our results indicate that cFLIP protects against the development of post-infarction cardiac remodelling. Thus, cFLIP gene delivery shows promise as a clinically powerful and novel therapeutic strategy for the treatment of heart failure after MI.

The 2011 Canadian Cardiovascular Society Heart Failure (HF) Guidelines Focused Update reviews the recently published clinical trials that will potentially impact on management. Also reviewed is the less studied but clinically important area of sleep apnea. Finally, patients with advanced HF represent a group of patients who pose major difficulties to clinicians. Advanced HF therefore is examined from the perspectives of HF complicated by renal failure, the role of palliative care, and the role of mechanical circulatory support (MCS). All of these topics are reviewed from a perspective of practical applications. Important new studies have demonstrated in less symptomatic HF patients that cardiac resynchronization therapy will be of benefit. As well, aldosterone receptor antagonists can be used with benefit in less symptomatic HF patients. The important role of palliative care and the need to address end-of-life issues in advanced HF are emphasized. Physicians need to be aware of the possibility of sleep apnea complicating the course of HF and the role of a sleep study for the proper assessment and management of the conditon. Patients with either acute severe or chronic advanced HF with otherwise good life expectancy should be referred to a cardiac centre capable of providing MCS. Furthermore, patients awaiting heart transplantation who deteriorate or are otherwise not likely to survive until a donor organ is found should be referred for MCS., (Copyright © 2011 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

The impact of cardiac dysfunction and heart failure is continuing to escalate in the developed world. Treatment of this heterogeneous condition has focused on the symptomatic stage, often after irreversible remodeling and functional impairment have occurred. Early identification of cardiac dysfunction would allow implementation of early intervention strategies to delay the progression or to prevent the onset of heart failure altogether. Although screening methods for asymptomatic cardiac dysfunction have yet to be optimized, a staged approach for patients with predisposing risk factors using serological biomarkers followed by noninvasive imaging techniques may be useful. Existing biomarkers for cardiac dysfunction include B-type natriuretic peptide, troponins, and C-reactive protein. Novel markers such as protein ST2, galectin-3, and various prohormones are emerging and may provide prognostic information that is incremental to conventional clinical evaluation. Monitoring myocardial mechanics and molecular processes through three-dimensional speckle tracking and hybrid imaging modalities, such as PET-CT, may provide insight into disease manifestation before overt structural and physiological abnormalities.

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.

Aims: Use of inotropic agents in patients with heart failure (HF) has been limited by adverse effects on outcomes. However, administration of positive inotropes at lower doses and concomitant treatment with beta-blockers might increase benefit-risk ratio. We investigated the effects of low doses of the positive inotrope enoximone on symptoms, exercise capacity, and major clinical outcomes in patients with advanced HF who were also treated with beta-blockers and other guideline-recommended background therapy., Methods and Results: The Studies of Oral Enoximone Therapy in Advanced HF (ESSENTIAL) programme consisted of two identical, randomized, double-blind, placebo-controlled trials that differed only by geographic location (North and South America: ESSENTIAL-I; Europe: ESSENTIAL-II). Patients with New York Heart Association class III-IV HF symptoms, left ventricular ejection fraction < or = 30%, and one hospitalization or two ambulatory visits for worsening HF in the previous year were eligible for participation in the trials. The trials had three co-primary endpoints: (i) the composite of time to all-cause mortality or cardiovascular hospitalization, analysed in the two ESSENTIAL trials combined; (ii) the 6 month change from baseline in the 6 min walk test distance (6MWTD); and (iii) the Patient Global Assessment (PGA) at 6 months, both analysed in each trial separately. ESSENTIAL-I and -II randomized 1854 subjects at 211 sites in 16 countries. In the combined trials, all-cause mortality and the composite, first co-primary endpoint did not differ between the two treatment groups [hazard ratio (HR) 0.97; 95% confidence interval (CI) 0.80-1.17; and HR 0.98; 95% CI 0.86-1.12, respectively, for enoximone vs. placebo]. The two other co-primary endpoints were analysed separately in the two ESSENTIAL trials, as prospectively designed in the protocol. The 6MWTD increased with enoximone, compared with placebo, in ESSENTIAL-I (P = 0.025, not reaching, however, the pre-specified criterion for statistical significance of P < 0.020), but not in ESSENTIAL-II. No difference in PGA was observed in either trial., Conclusion: Although low-dose enoximone appears to be safe in patients with advanced HF, major clinical outcomes are not improved.

Background: Higher blood pressure in acute heart failure has been associated with improved survival; however, the relationship between blood pressure and survival in stabilized patients at hospital discharge has not been established., Methods and Results: In 7448 patients with heart failure (75.2+/-11.5 years; 49.9% men) discharged from the hospital in Ontario, Canada, we examined the association of systolic blood pressure (SBP) and diastolic blood pressure with long-term survival. Parametric survival analysis was performed, and survival time ratios were determined according to discharge blood pressure group. A total of 25 427 person-years of follow-up were examined. In those with left ventricular ejection fraction < or =40%, median survival was decreased by 17% (survival time ratio, 0.83; 95% CI, 0.71 to 0.98; P=0.029) when discharge SBP was 100 to 119 mm Hg and decreased by 23% (survival time ratio, 0.77; 95% CI, 0.62 to 0.97; P=0.024) when discharge SBP was <100 mm Hg, compared with those in the reference range of 120 to 139 mm Hg. Survival time ratios were 0.75 (95% CI, 0.60 to 0.92; P=0.007) and 0.75 (95% CI, 0.53 to 1.07; P=0.12) when discharge SBPs were 140 to 159 and > or =160 mm Hg, respectively. In those with left ventricular ejection fraction >40%, survival time ratios were 0.69 (95% CI, 0.51 to 0.93), 0.83 (95% CI, 0.71 to 0.99), 0.95 (95% CI, 0.80 to 1.14), and 0.76 (95% CI, 0.61 to 0.95) for discharge SBPs <100, 100 to 119, 140 to 159, and > or =160 mm Hg, respectively., Conclusions: In this long-term population-based study of patients with heart failure, the association of discharge SBP with mortality followed a U-shaped distribution. Survival was shortened in those with reduced or increased values of discharge SBP.

The decision to anti-coagulate patients with heart failure (HF) is a difficult one, with limited data available to support clinical judgment. Thromboembolic complications, both arterial (stroke) and venous (deep vein thrombosis and pulmonary embolism), remain a significant cause of mortality and morbidity in this population. The pathophysiology of thrombogenesis in HF may be contextualized in the classic triad of stasis, endothelial dysfunction and hypercoagulability. Dilated cardiac chambers, reduced systolic function, and left ventricular aneurysm or thrombus have been suggested as potential contributing factors. HF is associated with activation of inflammatory and neuroendocrine pathways, leading to endothelial dysfunction and a prothrombotic state with dysregulated platelets and activation of the coagulation cascade. The epidemiology of thromboembolic events in HF is poorly defined. Most studies are retrospective and include patients with concurrent atrial fibrillation. The current body of health outcomes research is reviewed to identify the specific etiological factors, prevalence, and impact of thromboembolic events in this patient population. Conflicting analyses exist regarding the risks and benefits of prophylaxis in HF. The data surrounding several classes of therapeutic agents are synthesized. Recent clinical trials on anticoagulation and HF are reviewed, including WATCH, WASH, and WARCEF. The absence of compelling clinical trial data leaves many unanswered questions regarding systemic anticoagulation in patients with HF.

Gelsolin, a calcium-regulated actin severing and capping protein, is highly expressed in murine and human hearts after myocardial infarction and is associated with progression of heart failure in humans. The biological role of gelsolin in cardiac remodeling and heart failure progression after injury is not defined. To elucidate the contribution of gelsolin in these processes, we randomly allocated gelsolin knockout mice (GSN(-/-)) and wild-type littermates (GSN(+/+)) to left anterior descending coronary artery ligation or sham surgery. We found that GSN(-/-) mice have a surprisingly lower mortality, markedly reduced hypertrophy, smaller late infarct size, less interstitial fibrosis, and improved cardiac function when compared with GSN(+/+) mice. Gene expression and protein analysis identified significantly lower levels of deoxyribonuclease (DNase) I and reduced nuclear translocation and biological activity of DNase I in GSN(-/-) mice. Absence of gelsolin markedly reduced DNase I-induced apoptosis. The association of hypoxia-inducible factor (HIF)-1alpha with gelsolin and actin filaments cleaved by gelsolin may contribute to the higher activation of DNase. The expression pattern of HIF-1alpha was similar to that of gelsolin, and HIF-1alpha was detected in the gelsolin complex by coprecipitation and HIF-1alpha bound to the promoter of DNase I in both gel-shift and promoter activity assays. Furthermore, the phosphorylation of Akt at Ser473 and expression of Bcl-2 were significantly increased in GSN(-/-) mice, suggesting that gelsolin downregulates prosurvival factors. Our investigation concludes that gelsolin is an important contributor to heart failure progression through novel mechanisms of HIF-1alpha and DNase I activation and downregulation of antiapoptotic survival factors. Gelsolin inhibition may form a novel target for heart failure therapy.

Background: The influence of statin therapy in heart failure (HF) has been of considerable interest. The objective of this study was to determine if statins are associated with improved outcomes in patients discharged after hospitalization for HF., Methods: Patients admitted to Ontario hospitals between 1999 and 2001 with HF were identified in the Enhanced Feedback For Effective Cardiac Treatment study. Propensity score methods were used to assess 5-year outcomes in the overall cohort as well as in 4 subgroups: those with coronary artery disease (CAD) or without (NoCAD), and those with preserved ejection fraction (HFPEF) or with reduced ejection fraction (HFREF). Of the 6451 HF patients, 1121 were discharged with a prescription for a statin., Results: In propensity analysis stratified on matched pairs in a Cox proportional hazards model, statins were associated with improved mortality at 5 years overall (hazard ratio [HR] 0.85, P = .05) and in those with CAD (HR 0.79, P = .008). Similarly, statins were associated with lower risk of the combined end point in the CAD group (HR 0.85, P = .045)., Conclusions: Among patients with HF discharged from hospital, statin therapy was associated with improved outcomes, particularly in patients with CAD. Stratification by ejection fraction did not differentially impact the effect of statins in patients with HF.

The Canadian Cardiovascular Society published a comprehensive set of recommendations on the diagnosis and management of heart failure in January 2006. Based on feedback obtained through a national program of heart failure workshops and through active solicitation of stakeholders, several topics were identified because of their importance to the practicing clinician. Topics chosen for the present update include best practices for the diagnosis and management of right-sided heart failure, myocarditis and device therapy, and a review of recent important or landmark clinical trials. These recommendations were developed using the structured approach for the review and assessment of evidence adopted and previously described by the Society. The present update has been written from a clinical perspective to provide a user-friendly and practical approach. Specific clinical questions that are addressed include: What is right-sided heart failure and how should one approach the diagnostic work-up? What other clinical entities may masquerade as this nebulous condition and how can we tell them apart? When should we be concerned about the presence of myocarditis and how quickly should patients with this condition be referred to an experienced centre? Among the myriad of recently published landmark clinical trials, which ones will impact our standards of clinical care? The goals are to aid physicians and other health care providers to optimally treat heart failure patients, resulting in a measurable impact on patient health and clinical outcomes in Canada.

Acute heart failure syndromes (AHFS) have emerged as a leading public health problem worldwide, accounting for a substantial number of hospitalizations and a high utilization of resources. Although in-hospital mortality rates are relatively low, patients with AHFS have very high early after-discharge mortality and rehospitalization rates. The majority of patients admitted with AHFS have coronary artery disease (CAD), which independently has an adverse impact on prognosis. The initial in-hospital and after-discharge management of AHFS may be dependent on clinical presentation: AHFS in patients with underlying CAD or acute coronary syndromes (ACS) complicated by heart failure. In addition, the extent and severity of CAD and the presence of ischemia and/or stunned/hibernating myocardium should be assessed for optimal management. Although the overall management of AHFS with CAD may be similar to that in patients with ACS complicated by heart failure, for which specific guidelines exist, management of the former is less well defined. Prospective studies of the assessment and treatment of CAD in patients with AHFS are urgently needed.

Background and Objective: Angiotensin II type 1 receptor (AT(1)R) blockade reduces vascular oxidative stress but whether myocardial oxidative stress represents a mechanism for the beneficial effect of AT(1)R blockade in heart failure is unclear. Furthermore, the impact of AT(1)R blockade on the expression of angiotensin II receptors in heart failure has not been well documented. Accordingly, we examined the impact of the AT(1)R blocker candesartan on hemodynamics, left ventricular (LV) remodeling (echocardiography), oxidative stress, and tissue expression of AT(1)Rs and angiotensin II type 2 receptors (AT(2)Rs) in a canine model of pacing-induced heart failure., Methods and Results: Animals were randomized to rapid right ventricular-pacing (250 beats/min for 3 weeks) to severe heart failure and treated with candesartan (10 mg/kg daily, n = 8) or placebo (n = 8) from day 3 onwards, or no pacing (sham, n = 7). Candesartan significantly reduced mean pulmonary arterial and LV diastolic pressure, LV end-diastolic and end-systolic volume and ascites, increased cardiac output, dP/dt, and ejection fraction, while reversing the marked increase in aldehydes, a marker of oxidative stress, observed in the placebo group. Although candesartan did not alter LV AT(1)R protein expression compared to placebo or sham, it reversed the decrease in AT(2)R protein observed in the placebo group., Conclusion: Our results indicate that in the pacing model of heart failure, chronic AT(1)R blockade attenuates hemodynamic deterioration and limits LV remodeling and dysfunction, in part by reversing oxidative stress and AT(2)R downregulation.

Natriuretic peptide (NP) levels (B-type natriuretic peptide (BNP) and N-terminal proBNP) are now widely used in clinical practice and cardiovascular research throughout the world and have been incorporated into most national and international cardiovascular guidelines for heart failure. The role of NP levels in state-of-the-art clinical practice is evolving rapidly. This paper reviews and highlights ten key messages to clinicians: 1) NP levels are quantitative plasma biomarkers of heart failure (HF). 2) NP levels are accurate in the diagnosis of HF. 3) NP levels may help risk stratify emergency department (ED) patients with regard to the need for hospital admission or direct ED discharge. 4) NP levels help improve patient management and reduce total treatment costs in patients with acute dyspnoea. 5) NP levels at the time of admission are powerful predictors of outcome in predicting death and re-hospitalisation in HF patients. 6) NP levels at discharge aid in risk stratification of the HF patient. 7) NP-guided therapy may improve morbidity and/or mortality in chronic HF. 8) The combination of NP levels together with symptoms, signs and weight gain assists in the assessment of clinical decompensation in HF. 9) NP levels can accelerate accurate diagnosis of heart failure presenting in primary care. 10) NP levels may be helpful to screen for asymptomatic left ventricular dysfunction in high-risk patients.

One of the most important comorbidities in heart failure is renal dysfunction. Diminished estimated glomerular filtration rate is a potent predictor of cardiovascular mortality and complications. On the other hand, worsening heart failure or acute decompensated heart failure can accelerate worsening of renal function--the so-called cardiorenal syndrome. Risk factors include hypertension, diabetes, elderly age, and prior history of heart or renal failure. The pathophysiology of the cardiorenal syndrome involves intrarenal hemodynamics, transrenal perfusion pressure and systemic neurohormonal factors. Clinical management of the patient with cardiorenal syndrome includes the challenge of diuretic resistance, which may involve correcting the underlying cause, combination diuretics or diuretic infusions. The key to improved outcome is the optimization of proven heart failure therapies. The use of vasodilator therapy is the current mainstay of treatment. Nesiritide, or recombinant B-type natriuretic peptide, has courted controversy regarding its role in cardiorenal syndrome. However, data are emerging that low doses appear to be renal-protective. Other more recent strategies include ultrafiltration, vasopressin antagonists and adenosine antagonists. All of these newer modalities promise more rapid volume removal, but their ultimate impact on survival or preservation of renal function is unknown at the present time. Because of the complex nature of these patients, and the compromised outcome, it is important that cardiologists, nephrologists and internists all work together toward the common goal of protecting the patient with cardiorenal syndrome, and use the best available evidence for management.

Objectives: This study evaluated whether a xanthine oxidase (XO) inhibitor, oxypurinol, produces clinical benefits in patients with New York Heart Association functional class III to IV heart failure due to systolic dysfunction receiving optimal medical therapy., Background: Increased XO activity may contribute to heart failure pathophysiology., Methods: Patients (n = 405) were randomized to oxypurinol (600 mg/day) or placebo. Efficacy at 24 weeks was assessed using a composite end point comprising heart failure morbidity, mortality, and quality of life., Results: The percentage of patients characterized as improved, unchanged, or worsened did not differ between those receiving oxypurinol or placebo. Oxypurinol reduced serum uric acid (SUA) by approximately 2 mg/dl (p < 0.001). In a subgroup analysis, patients with elevated SUA (>9.5 mg/dl, n = 108) responded favorably to oxypurinol (p = 0.02 for interaction term), whereas oxypurinol patients with SUA <9.5 mg/dl exhibited a trend towards worsening. In addition, SUA reduction to oxypurinol correlated with favorable clinical response. Within the entire oxypurinol patient cohort, those characterized as either improved or unchanged had significantly greater reductions in SUA compared with patients who worsened (-2.3 +/- 2.1 mg/dl vs. -1.0 +/- 1.9 mg/dl, p = 0.0006). In placebo patients, lower baseline SUA, but not change in SUA, correlated with improved clinical outcome., Conclusions: Oxypurinol did not produce clinical improvements in unselected patients with moderate-to-severe heart failure. However, post-hoc analysis suggests that benefits occur in patients with elevated SUA in a manner correlating with the degree of SUA reduction. Serum uric acid may serve as a valuable biomarker to target XO inhibition in heart failure. (Oxypurinol Compared With Placebo for Class III-IV NYHA Congestive Heart Failure; NCT00063687).

Aims: The maladaptive response to biomechanical stress is a fundamental response in heart disease. Loss of the 3'-lipid phosphatase, phosphatase and tensin homolog deleted on chromosome ten (PTEN), is associated with increased phosphorylation of Akt/protein kinase B and glycogen synthase kinase-beta. We hypothesize that these key changes will halt the development of pathological hypertrophy and the progression to heart failure in response to pressure overload., Methods and Results: In mice, muscle-specific knockout of PTEN, mckCRE-PTEN(flox/flox) (PTEN KO), resulted in basal hypertrophy and mild reduction in left ventricular (LV) systolic function. Male mice were subjected to aortic banding (AB) or sham operation. In contrast to mckCRE-PTEN(+/+) control mice, pressure overload in PTEN KO mice resulted in reduced pathological hypertrophy, less interstitial fibrosis, and reduced apoptosis with a marked preservation of LV function. Western blot analysis of mitogen-activated protein kinase (MAPK) signalling showed equivalent phosphorylation of extracellular signal-regulated kinase (ERK)1 and ERK2 with markedly reduced phosphorylation of jun N-terminal kinase (JNK)1 and JNK2, and p38 in PTEN KO mice subjected to AB. Loss of PTEN was associated with increased expression of the proangiogenic factors, vascular endothelial growth factor-A and angiopoietin-2, with preservation of the myocardial capillary density in response to pressure overload. Moreover, banded PTEN KO mice maintained the expression of several key metabolic genes that are known to be dysregulated in heart failure. In contrast, a subpressor dose of the G protein-coupled receptor (GPCR) agonist angiotensin II (Ang II) leads to increased pathological hypertrophy and MAPK activation in PTEN KO mice., Conclusion: Loss of PTEN prevents the development of maladaptive ventricular remodelling with preservation of angiogenesis and metabolic gene expression in response to pressure overload but not in response to the GPCR agonist, Ang II. Inhibition of PTEN signalling in the heart may represent a novel approach to slow the progression of heart failure in response to pathological biomechanical stress.

Background: Both neurohormonal derangements and alterations in the myocardial extracellular matrix are thought to contribute to adverse ventricular remodelling that results in worsening heart failure (HF). There is also emerging preclinical information to suggest that these signalling pathways mutually regulate in HF., Aim: To assess the relationships between plasma levels of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinase (TIMP), and neurohormonal profiles in chronic HF., Methods and Results: In this substudy of 184 HF patients enrolled in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, plasma norepinephrine and epinephrine were measured with HPLC; atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), angiotensin II, aldosterone, and endothelin-1 were measured with immunoassays; MMP-2, MMP-9, and TIMP-1 were measured with 2-site sandwich ELISA assays. We used Spearman's rank correlation to examine the relationships between plasma MMP and neurohormone levels. Circulating ANP, BNP, and endothelin-1 levels were positively correlated with MMP-2 and TIMP-1 levels. Plasma level of aldosterone showed a weak positive correlation with MMP-9, but there was no significant correlation between angiotensin II, epinephrine or norepinephrine and MMP-2, MMP-9, or TIMP-1., Conclusions: These findings suggest that specific neurohormones and extracellular matrix modulators may play a coordinated role in the pathogenesis of HF.

Heart failure is a clinical syndrome that normally requires health care to be provided by both specialists and nonspecialists. This is advantageous because patients benefit from complementary skill sets and experience, but can present challenges in the development of a common, shared treatment plan. The Canadian Cardiovascular Society published a comprehensive set of recommendations on the diagnosis and management of heart failure in January 2006, and on the prevention, management during intercurrent illness or acute decompensation, and use of biomarkers in January 2007. The present update builds on those core recommendations. Based on feedback obtained through a national program of heart failure workshops during 2006 and 2007, several topics were identified as priorities because of the challenges they pose to health care professionals. New evidence-based recommendations were developed using the structured approach for the review and assessment of evidence that was adopted and previously described by the Society. Specific recommendations and practical tips were written for best practices during the transition of care of heart failure patients, and the recognition, investigation and treatment of some specific cardiomyopathies. Specific clinical questions that are addressed include: What information should a referring physician provide for a specialist consultation? What instructions should a consultant provide to the referring physician? What processes should be in place to ensure that the expectations and needs of each physician are met? When a cardiomyopathy is suspected, how can it be recognized, how should it be investigated and diagnosed, how should it be treated, when should the patient be referred, and what special tests are available to assist in the diagnosis and treatment? The goals of the present update are to translate best evidence into practice, apply clinical wisdom where evidence for specific strategies is weaker, and aid physicians and other health care providers to optimally treat heart failure patients, resulting in a measurable impact on patient health and clinical outcomes in Canada.

Apelin constitutes a novel endogenous peptide system suggested to be involved in a broad range of physiological functions, including cardiovascular function, heart development, control of fluid homeostasis, and obesity. Apelin is also a catalytic substrate for angiotensin-converting enzyme 2, the key severe acute respiratory syndrome receptor. The in vivo physiological role of Apelin is still elusive. Here we report the generation of Apelin gene-targeted mice. Apelin mutant mice are viable and fertile, appear healthy, and exhibit normal body weight, water and food intake, heart rates, and heart morphology. Intriguingly, aged Apelin knockout mice developed progressive impairment of cardiac contractility associated with systolic dysfunction in the absence of histological abnormalities. We also report that pressure overload induces upregulation of Apelin expression in the heart. Importantly, in pressure overload-induced heart failure, loss of Apelin did not significantly affect the hypertrophy response, but Apelin mutant mice developed progressive heart failure. Global gene expression arrays and hierarchical clustering of differentially expressed genes in hearts of banded Apelin(-/y) and Apelin(+/y) mice showed concerted upregulation of genes involved in extracellular matrix remodeling and muscle contraction. These genetic data show that the endogenous peptide Apelin is crucial to maintain cardiac contractility in pressure overload and aging.

Heart failure is common, yet it is difficult to treat. It presents in many different guises and circumstances in which therapy needs to be individualized. The Canadian Cardiovascular Society published a comprehensive set of recommendations in January 2006 on the diagnosis and management of heart failure, and the present update builds on those core recommendations. Based on feedback obtained through a national program of heart failure workshops during 2006, several topics were identified as priorities because of the challenges they pose to health care professionals. New evidence-based recommendations were developed using the structured approach for the review and assessment of evidence adopted and previously described by the Society. Specific recommendations and practical tips were written for the prevention of heart failure, the management of heart failure during intercurrent illness, the treatment of acute heart failure, and the current and future roles of biomarkers in heart failure care. Specific clinical questions that are addressed include: which patients should be identified as being at high risk of developing heart failure and which interventions should be used? What complications can occur in heart failure patients during an intercurrent illness, how should these patients be monitored and which medications may require a dose adjustment or discontinuation? What are the best therapeutic, both drug and nondrug, strategies for patients with acute heart failure? How can new biomarkers help in the treatment of heart failure, and when and how should BNP be measured in heart failure patients? The goals of the present update are to translate best evidence into practice, to apply clinical wisdom where evidence for specific strategies is weaker, and to aid physicians and other health care providers to optimally treat heart failure patients to result in a measurable impact on patient health and clinical outcomes in Canada.

Background: The importance of heart failure with preserved ejection fraction is increasingly recognized. We conducted a study to evaluate the epidemiologic features and outcomes of patients with heart failure with preserved ejection fraction and to compare the findings with those from patients who had heart failure with reduced ejection fraction., Methods: From April 1, 1999, through March 31, 2001, we studied 2802 patients admitted to 103 hospitals in the province of Ontario, Canada, with a discharge diagnosis of heart failure whose ejection fraction had also been assessed. The patients were categorized in three groups: those with an ejection fraction of less than 40 percent (heart failure with reduced ejection fraction), those with an ejection fraction of 40 to 50 percent (heart failure with borderline ejection fraction), and those with an ejection fraction of more than 50 percent (heart failure with preserved ejection fraction). Two groups were studied in detail: those with an ejection fraction of less than 40 percent and those with an ejection fraction of more than 50 percent. The main outcome measures were death within one year and readmission to the hospital for heart failure., Results: Thirty-one percent of the patients had an ejection fraction of more than 50 percent. Patients with heart failure with preserved ejection fraction were more likely to be older and female and to have a history of hypertension and atrial fibrillation. The presenting history and clinical examination findings were similar for the two groups. The unadjusted mortality rates for patients with an ejection fraction of more than 50 percent were not significantly different from those for patients with an ejection fraction of less than 40 percent at 30 days (5 percent vs. 7 percent, P=0.08) and at 1 year (22 percent vs. 26 percent, P=0.07); the adjusted one-year mortality rates were also not significantly different in the two groups (hazard ratio, 1.13; 95 percent confidence interval, 0.94 to 1.36; P=0.18). The rates of readmission for heart failure and of in-hospital complications did not differ between the two groups., Conclusions: Among patients presenting with new-onset heart failure, a substantial proportion had an ejection fraction of more than 50 percent. The survival of patients with heart failure with preserved ejection fraction was similar to that of patients with reduced ejection fraction., (Copyright 2006 Massachusetts Medical Society.)

Heart failure remains a common diagnosis, especially in older individuals. It continues to be associated with significant morbidity and mortality, but major advances in both diagnosis and management have occurred and will continue to improve symptoms and other outcomes in patients. The Canadian Cardiovascular Society published its first consensus conference recommendations on the diagnosis and management of heart failure in 1994, followed by two brief updates, and reconvened this consensus conference to provide a comprehensive review of current knowledge and management strategies. New clinical trial evidence and meta-analyses were critically reviewed by a multidisciplinary primary panel who developed both recommendations and practical tips, which were reviewed by a secondary panel. The resulting document is intended to provide practical advice for specialists, family physicians, nurses, pharmacists and others who are involved in the care of heart failure patients. Management of heart failure begins with an accurate diagnosis, and requires rational combination drug therapy, individualization of care for each patient (based on their symptoms, clinical presentation and disease severity), appropriate mechanical interventions including revascularization and devices, collaborative efforts among health care professionals, and education and cooperation of the patient and their immediate caregivers. The goal is to translate best evidence-based therapies into clinical practice with a measureable impact on the health of heart failure patients in Canada.

Cytokine and extracellular matrix (ECM) homeostasis are distinct systems that are each dysregulated in heart failure. Here we show that tissue inhibitor of metalloproteinase (TIMP)-3 is a critical regulator of both systems in a mouse model of left ventricular (LV) dilation and dysfunction. Timp-3(-/-) mice develop precipitous LV dilation and dysfunction reminiscent of dilated cardiomyopathy (DCM), culminating in early onset of heart failure by 6 weeks, compared with wild-type aortic-banding (AB). Timp-3 deficiency resulted in increased TNFalpha converting enzyme (TACE) activity within 6 hours after AB leading to enhanced tumor necrosis factor-alpha (TNFalpha) processing. In addition, TNFalpha production increased in timp-3(-/-)-AB myocardium. A significant elevation in gelatinase and collagenase activities was observed 1 week after AB, with localized ECM degradation in timp-3(-/-)-AB myocardium. Timp-3(-/-)/tnfalpha(-/-) mice were generated and subjected to AB for comparative analyses with timp-3(-/-)-AB mice. This revealed the critical role of TNFalpha in the early phase of LV remodeling, de novo expression of Matrix metalloproteinases (MMP)-8 in the absence of TNFalpha, and highlighted the importance of interstitial collagenases (MMP-2, MMP-13, and MT1-MMP) for cardiac ECM degradation. Ablation of TNFalpha, or limiting MMP activity with a synthetic MMP inhibitor (PD166793), each partially attenuated LV dilation and cardiac dysfunction in timp-3(-/-)-AB mice. Notably, combining TNFalpha ablation with MMP inhibition completely rescued heart disease in timp-3(-/-)-AB mice. This study provides a basis for anti-TNFalpha and MMP inhibitor combination therapy in heart disease.