Executive Summary: HFSA 2010 Comprehensive Heart Failure Practice Guideline

Article Outline

• Abstract
• Section 1: Development and Implementation of a Comprehensive Heart Failure Practice Guideline
  • HFSA Guideline Approach to Medical Evidence
    • Strength of Evidence A
    • Strength of Evidence B
    • Strength of Evidence C
  • HFSA Guideline Approach to Strength of Recommendation
    • Determining Strength
    • Totality of Evidence
    • Scale of Strength
  • Process of Guideline Development
    • Consensus
    • Dissemination and Continuity
  • Summary
• Section 2: Conceptualization and Working Definition of Heart Failure
  • Additional Definitions
• Section 3: Prevention of Ventricular Remodeling, Cardiac Dysfunction, and Heart Failure
  • Recommendations for Patients With Risk Factors for Ventricular Remodeling, Cardiac Dysfunction, and Heart Failure
• Section 4. Evaluation of Patients for Ventricular Dysfunction and Heart Failure
  • Patients at Risk for Heart Failure
  • Recommendations for Evaluation of Patients at Risk for Heart Failure
  • Patients Suspected of Having HF
  • Recommendations for Evaluation of Patients Suspected of Having HF
  • Patients With Established HF
  • Recommendations for the Evaluation of Patients With Established HF
• Section 5: Management of Asymptomatic Patients With Reduced Left Ventricular Ejection Fraction
  • Recommendations for the Management of Asymptomatic Patients With Reduced LVEF
• Section 6: Nonpharmacologic Management and Health Care Maintenance in Patients With Chronic Heart Failure
  • Recommendations for Diet and Nutrition
  • Recommendations for Other Therapies
  • Recommendations for Specific Activity and Lifestyle Issues
  • Recommendations for Routine Health Care Maintenance
  • Recommendations for Exercise Testing/Exercise Training
• Section 7: Heart Failure in Patients With Reduced Ejection Fraction
  • Recommendations for ACE-inhibitors
  • Recommendations for Alternatives to ACE-inhibitors
  • Recommendations for Angiotensin Receptor Blockers
  • Recommendations for Beta Adrenergic Receptor Blockers
  • Recommendations for Combination ACE-inhibitor, ARB, and Beta Adrenergic Receptor Blocker Therapy
  • Recommendations for Aldosterone Antagonists
  • Recommendations for Oral Nitrates and Hydralazine
  • Recommendations for Optimal Use of Multi-Drug Therapy
  • Recommendations for Diuretic Therapy
  • Recommendations for Digoxin
  • Recommendations for Anticoagulation and Antiplatelet Drugs
  • Recommendations for Amiodarone Therapy
• Section 8: Disease Management, Advance Directives, and End-of-Life Care in Heart Failure
  • Recommendations for Education and Counseling
  • Recommendations for Disease Management Programs
  • Recommendations for Advance Directives and End-of-Life Care
• Section 9: Electrophysiology Testing and the Use of Devices in Heart Failure
  • Recommendations for General Electrophysiology Testing
  • Recommendations for Electrophysiology Testing and Evaluation of Syncope
  • Recommendations for Prophylactic ICD Placement
  • Recommendations for Biventricular Resynchronization Pacing
  • Recommendations for Dual Chamber Pacemakers
• Section 10: Surgical Approaches to the Treatment of Heart Failure
  • Recommendations for Surgical Approaches
• Section 11: Evaluation and Management of Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction
  • Recommendations for Patients With Heart Failure and Preserved LVEF
• Section 12: Evaluation and Management of Patients With Acute Decompensated Heart Failure
  • Recommendations for Acute Decompensated Heart Failure
• Section 13: Evaluation and Therapy for Heart Failure in the Setting of Ischemic Heart Disease
  • Recommendations for Heart Failure in the Setting of Ischemic Heart Disease
• Section 14: Managing Patients With Hypertension and Heart Failure
  • Recommendation for Patients With Hypertension and Preserved LVEF and Asymptomatic LVH, or for Patients With Hypertension and HF With Preserved LVEF (Stage B)
  • Recommendations for Patients With Hypertension and Asymptomatic LV Dysfunction With LV Dilation and a Low LVEF
  • Recommendations for Patients With Hypertension and Symptomatic LV Dysfunction With LV Dilation and Low LVEF
• Section 15: Management of Heart Failure in Special Populations
  • Recommendations
• Section 16: Myocarditis: Current Treatment
  • Recommendations
• Section 17: Genetic Evaluation of Cardiomyopathy∗
  • Recommendations for the Genetic Evaluation of Cardiomyopathy
• Acknowledgment
• Disclosures
• Appendix A. 
• Appendix B. 
• Appendix C. 
• References
• Copyright

Abstract 

Heart failure (HF) is a syndrome characterized by high mortality, frequent hospitalization, reduced quality of life, and a complex therapeutic regimen. Knowledge about HF is accumulating so rapidly that individual clinicians may be unable to readily and adequately synthesize new information into effective strategies of care for patients with this syndrome. Trial data, though valuable, often do not give direction for individual patient management. These characteristics make HF an ideal candidate for practice guidelines. The 2010 Heart Failure Society of America comprehensive practice guideline addresses the full range of evaluation, care, and management of patients with HF.

Key Words: Heart failure, practice guidelines

Guideline Committee Members

JoAnn Lindenfeld, MD¹ (Chair)

Nancy M. Albert, RN, PhDDebra K. Moser, RN, DNSc

John P. Boehmer, MDJoseph G. Rogers, MD

Sean P. Collins, MD, MScRandall C. Starling, MD, MPH

Justin A. Ezekowitz, MBBChWilliam G. Stevenson, MD

Michael M. Givertz, MDW. H. Wilson Tang, MD

Stuart D. Katz, MD John R. Teerlink, MD

Marc Klapholz, MDMary N. Walsh, MD

Executive Council

Douglas L. Mann, MD, President

Inder S. Anand, MDSteven R. Houser, PhD

J. Malcolm O. Arnold, MDMariell L. Jessup, MD

John C. Burnett, Jr., MDBarry M. Massie, MD

John Chin, MDMandeep R. Mehra, MD

Jay N. Cohn, MDMariann R. Piano RN, PhD

Thomas Force, MDClyde W. Yancy, MD

Barry H. Greenberg, MDMichael R. Zile, MD

Table of Contents

Section 1: Development and Implementation of a Comprehensive Heart Failure Practice Guideline476

Section 2: Conceptualization and Working Definition of Heart Failure479

Section 3: Prevention of Ventricular Remodeling, Cardiac Dysfunction, and Heart Failure480

Section 4. Evaluation of Patients for Ventricular Dysfunction and Heart Failure481

Section 5: Management of Asymptomatic Patients with Reduced Left Ventricular Ejection Fraction484

Section 6: Nonpharmacologic Management and Health Care Maintenance in Patients with Chronic Heart Failure485

Section 7: Heart Failure in Patients with Reduced Ejection Fraction486

Section 8: Disease Management, Advance Directives, and End-of-Life Care in Heart Failure492

Section 9: Electrophysiology Testing and the Use of Devices in Heart Failure494

Section 10: Surgical Approaches to the Treatment of Heart Failure495

Section 11: Evaluation and Management of Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction496

Section 12: Evaluation and Management of Patients with Acute Decompensated Heart Failure497

Section 13: Evaluation and Therapy for Heart Failure in the Setting of Ischemic Heart Disease500

Section 14: Managing Patients with Hypertension and Heart Failure502

Section 15: Management of Heart Failure in Special Populations502

Section 16: Myocarditis: Current Treatment503

Section 17: Genetic Evaluation of Cardiomyopathy^∗503

Acknowledgement505

References506

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Section 1: Development and Implementation of a Comprehensive Heart Failure Practice Guideline 

Heart failure (HF) is a syndrome characterized by high mortality, frequent hospitalization, poor quality of life, multiple comorbidities, and a complex therapeutic regimen. Knowledge about HF is accumulating so rapidly that individual clinicians may be unable to readily and adequately synthesize new information into effective principles of care for patients with this syndrome. Trial data, though valuable, often do not give adequate direction for individual patient management.

Given the complex and changing picture of HF and the accumulation of evidence-based HF therapy, it is not possible for the clinician to rely solely on personal experience and observation to guide therapeutic decisions. The situation is exacerbated because HF is now a chronic condition in most patients, meaning that the outcome of therapeutic decisions might not be apparent for several years. The prognosis of individual patients differs considerably, making it difficult to generalize. Treatments might not dramatically improve symptoms of the disease process, yet might provide important reductions or delays in morbid events and deaths. The assessment of specific therapeutic outcomes is complicated by the potential differential impact of various cotherapies.

The complexity of HF, its high prevalence in society, and the availability of many therapeutic options make it an ideal candidate for practice guidelines. Additional assumptions driving the development of HF guidelines are presented in Table 1.1.

Table 1.1. Assumptions Underlying HFSA Practice Guideline

The first HF guideline developed by the Heart Failure Society of America (HFSA) had a narrow scope, concentrating on the pharmacologic treatment of chronic, symptomatic left ventricular dysfunction.¹ It did not consider subsets of the clinical syndrome of HF, such as acute decompensated HF and “diastolic dysfunction,” or issues such as prevention. The subsequent comprehensive clinical practice guideline published in 2006 addressed a full range of topics including prevention, evaluation, disease management, and pharmacologic and device therapy for patients with HF.² The 2010 guideline updates and expands each of these areas and adds a section on the Genetic Evaluation of Cardiomyopathy published separately in 2009.³ The discussion of end of life management has also been considerably expanded. Appendix A is a comparison of the 2006 and 2010 guideline, summarizing the modifications, additions, and deletions in the guideline recommendations. Appendix B is a list of acronyms (including clinical trials) used in the 2010 guideline.

HFSA Guideline Approach to Medical Evidence 

Two considerations are critical in the development of practice guidelines: assessing strength of evidence and determining strength of recommendation. Strength of evidence is determined both by the type of evidence available and the assessment of validity, applicability, and certainty of a specific type of evidence. Following the lead of previous guidelines, strength of evidence in this guideline is heavily dependent on the source or type of evidence used. The HFSA guideline process has used three grades (A, B, or C) to characterize the type of evidence available to support specific recommendations (Table 1.2).

Table 1.2. Relative Weight of Evidence Used to Develop HFSA Practice Guideline

It must be recognized, however, that the evidence supporting recommendations is based largely on population responses that may not always apply to individuals within the population. Therefore, data may support overall benefit of one treatment over another but cannot exclude that some individuals within the population may respond better to the other treatment. Thus, guidelines can best serve as evidence-based recommendations for management, not as mandates for management in every patient. Furthermore, it must be recognized that trial data on which recommendations are based have often been carried out with background therapy not comparable to therapy in current use. Therefore, physician decisions regarding the management of individual patients may not always precisely match the recommendations. A knowledgeable physician who integrates the guidelines with pharmacologic and physiologic insight and knowledge of the individual being treated should provide the best patient management.

Randomized controlled clinical trials provide what is considered the most valid form of guideline evidence. Some guidelines require at least 2 positive randomized clinical trials before the evidence for a recommendation can be designated level A. The HFSA guideline committee has occasionally accepted a single randomized, controlled, outcome-based clinical trial as sufficient for level A evidence when the single trial is large with a substantial number of endpoints and has consistent and robust outcomes. However, randomized clinical trial data, whether derived from one or multiple trials, have not been taken simply at face value. They have been evaluated for: (1) endpoints studied, (2) level of significance, (3) reproducibility of findings, (4) generalizability of study results, and (5) sample size and number of events on which outcome results are based.

The HFSA guideline process also considers evidence arising from cohort studies or smaller clinical trials with physiologic or surrogate endpoints. This level B evidence is derived from studies that are diverse in design and may be prospective or retrospective in nature. They may involve subgroup analyses of clinical trials or have a case control or propensity design using a matched subset of trial populations. Dose-response studies, when available, may involve all or a portion of the clinical trial population. Evidence generated from these studies has well-recognized, inherent limitations. Nevertheless, their value is enhanced through attention to factors such as pre-specification of hypotheses, biologic rationale, and consistency of findings between studies and across different populations.

The present HFSA guideline makes extensive use of expert opinion, or C-level evidence. The need to formulate recommendations based on level C evidence is driven primarily by a paucity of scientific evidence in many areas critical to a comprehensive guideline. For example, the diagnostic process and the steps used to evaluate and monitor patients with established HF have not been the subject of clinical studies that formally test the validity of one approach versus another. In areas such as these, recommendations must be based on expert opinion or go unaddressed.

The value of expert opinion as a form of evidence remains disputed. Many contend that expert opinion is a weak form of observational evidence, based on practice experience and subject to biases and limitations. Advocates believe expert opinion represents a complex synthesis of observational insights into disease pathophysiology and the benefits of therapy in broad populations of patients. They stress the value of the interchange of experience and ideas among colleagues, who collectively treat thousands of patients. Through contact with numerous individual health care providers who may discuss patients with them, experts are exposed to rare safety issues and gain insight into the perceptions of practitioners concerning the efficacy of particular treatments across a wide spectrum of HF.

Despite the case that can be made for its value, recommendations based on expert opinion alone have been limited to those circumstances when a definite consensus could be reached across the guideline panel and reviewers.

HFSA Guideline Approach to Strength of Recommendation 

Although level of evidence is important, the strength given to specific recommendations is critical. The process used to determine the strength of individual recommendations is complex. The goal of guideline development is to achieve the best recommendations for evaluation and management, considering not only efficacy, but the cost, convenience, side effect profile, and safety of various therapeutic approaches. The HFSA guideline committee often determined the strength of a recommendation by the “totality of evidence,” which is a synthesis of all types of available data, pro and con, about a particular therapeutic option.

Totality of evidence includes not only results of clinical trials, but also expert opinion and findings from epidemiologic and basic science studies. Agreement among various types of evidence, especially from different methodologies, increases the likelihood that a particular therapy is valuable. Although many equate evidence-based medicine with the results of a few individual clinical trials, the best judgment seems to be derived from a careful analysis of all available trial data combined with integration of results from the basic laboratory and the findings of epidemiologic studies.

The HFSA guideline employs the categorization for strength of recommendation outlined in Table 1.3. There are several degrees of favorable recommendations and a single category for therapies felt to be not effective. The phrase “is recommended” should be taken to mean that the recommended therapy or management process should be followed as often as possible in individual patients. Exceptions are carefully delineated. “Should be considered” means that a majority of patients should receive the intervention, with some discretion involving individual patients. “May be considered” means that individualization of therapy is indicated (Table 1.3). When the available evidence is considered to be insufficient or too premature, or consensus fails, issues are labeled unresolved and included as appropriate at the end of the relevant section.

Table 1.3. HFSA System for Classifying the Strength of Recommendations

Process of Guideline Development 

Key steps in the development of this guideline are listed in Table 1.4. Having determined the broad scope of the current guideline, subcommittees of the guideline committee were formed for each section of the guideline. A literature search with relevant key words and phrases for each guideline section were provided to members of the subcommittees and the full Guideline Committee. Members of each subcommittee were asked to review the search and identify any additional relevant medical evidence for each assigned section. Changes in recommendation and background were carried out by each subcommittee with conference calls directed by the Guideline Committee chair. Each section was presented for comments and consensus approval to the Guideline Committee. Once subsections were complete, the Executive Council reviewed and commented on each section and these comments were returned to the Guideline Committee for changes and once complete, for final approval by the Executive Council.

Table 1.4. Steps in the Development of the 2010 HFSA Practice Guideline

The development of a guideline involves the selection of individuals with expertise and experience to drive the process of formulating specific recommendations and producing a written document. The role of these experts goes well beyond the formulation of recommendations supported by expert opinion.

Experts involved in the guideline process must function as a collective, not as isolated individuals. Expert opinion is not always unanimous. Interpretations of data vary. Disagreements arise over the generalizability and applicability of trial results to various patient subgroups. Experts are influenced by their own experiences with particular therapies, but still generally agree on the clinical value of trial data. Discomfort with the results of trials reported as positive or negative generally focus on factors that potentially compromise the evidence. Unfortunately, there are no absolute rules for downgrading or upgrading trial results or for deciding that the limitations of the trial are sufficient to negate what has been regarded as a traditionally positive or negative statistical result.

The HFSA Guideline Committee sought resolution of difficult cases through consensus building. An open, dynamic discussion meant that no single voice was allowed to dominate. Written documents were essential to this process, because they provided the opportunity for feedback from all members of the group. On occasion, consensus of opinion was sufficient to override positive or negative results of almost any form of evidence. The HFSA process had a strong commitment to recommendations based on objective evidence rigorously reviewed by a panel of experts.

Issues that caused difficulty for the HFSA guideline process were some of the more important ones faced by the committee, because they mirrored those that are often most challenging to clinicians in day-to-day practice. The foundation of the HFSA guideline process was the belief that the careful judgment of recognized opinion leaders in these controversial areas is more likely to be correct than ad hoc decisions made “on the spot” by physicians in practice.

The involvement of many groups in the development of this guideline helped avoid the introduction of bias, which can be personal, practice-based, or based on financial interest. Committee members and reviewers from the Executive Council received no direct financial support from the HFSA or any other source for the development of the guideline. Support was provided by the HFSA administrative staff, but the writing of the document was performed on a volunteer basis primarily by the Committee. Financial relationships that might represent conflicts of interest were collected annually from all members of the Guideline Committee and the Executive Council. Current relationships are shown in Appendix C.

The value of a practice guideline is significantly influenced by the scope of its dissemination. The first and second HFSA guidelines were available on the Internet, and thousands of copies were downloaded. The current document will be implemented on the Internet both for file transfer and as a hypertext source of detailed knowledge concerning HF.

An important final consideration is the continuity of the guideline development process. The intent is to create a “living document” that will be updated and amended as necessary to ensure continuing relevance. The rapid development of new knowledge in HF from basic and clinical research and the continuing evolution of pharmacologic and device therapy for this condition provides a strong mandate for timely updates. The HFSA intends to undertake targeted reviews and updates in areas where new research has implications for practice. Section 17: The Genetic Evaluation of Cardiomyopathy is an example of this policy.

Summary 

Practice guidelines have become a major part of the clinical landscape and seem likely to become more rather than less pervasive. Some may perceive guidelines as another mechanism for process management or as another instrument for cost control. But there is a more patient-centered rationale for their development, especially for a common, potentially debilitating, and often fatal syndrome such as HF. Despite advances in clinical trial methodology and the extensive use of studies to evaluate therapeutics and the care process, essential elements of the management process remain undefined for many clinical problems. HF is no exception. Traditionally, management guidelines were determined on an ad hoc basis by physicians and other health care providers in the field. The development and utilization of practice guidelines has emerged as an alternative strategy. The methodology of guideline development needs improvement, but when these documents are properly conceived and formulated, their importance to patient care seems evident. This HFSA guideline on HF is designed as a “living document,” which will continue to serve as a resource for helping patients with HF.

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Section 2: Conceptualization and Working Definition of Heart Failure 

HF remains a major and growing societal problem despite advances in detection and therapy.⁴, ⁵, ⁶, ⁷ However, there is no widely accepted characterization and definition of HF, probably because of the complexity of the syndrome. The conceptualization and working definition of HF presented here emerged as these guidelines were developed. They are critical to understanding HF and approaching its treatment appropriately.

Conceptual Background. HF is a syndrome rather than a primary diagnosis. It has many potential etiologies, diverse clinical features, and numerous clinical subsets. Patients may have a variety of primary cardiovascular diseases and never develop cardiac dysfunction, and those in whom cardiac dysfunction is identified through testing may never develop clinical HF. In addition to cardiac dysfunction, other factors, such as vascular stiffness, dyssynchrony, and renal sodium handling, play major roles in the manifestation of the syndrome of HF.

Patients at risk for many cardiovascular diseases are at risk for HF. Early identification and treatment of risk factors is perhaps the most significant step in limiting the public health impact of HF.⁸, ⁹, ¹⁰ Emphasis on primary and secondary prevention is particularly critical because of the difficulty of successfully treating left ventricular (LV) dysfunction, especially when severe.⁸ Current therapeutic advances in the treatment of HF do not make prevention any less important.

Although HF is progressive, current therapy may provide stability and even reversibility. The inexorable progression of HF from LV remodeling and dysfunction is no longer inevitable. Prolonged survival with mild to moderate LV dysfunction is now possible. Therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), beta blockers, and cardiac resynchronization therapy (CRT) can lead to slowing or to partial reversal of remodeling.

Because of this prolonged survival, comorbid conditions, such as coronary artery disease (CAD) or renal failure, can progress, complicating treatment. Given this prolonged survival, considerable attention is devoted in this guideline to disease management, the use of multidrug therapy, and the management of patients with HF at the end of life.

Working Definition. Although HF may be caused by a variety of disorders, the following comprehensive guideline and this working definition focus on HF primarily from the loss or dysfunction of myocardial muscle or interstitium.

HF is a syndrome caused by cardiac dysfunction, generally resulting from myocardial muscle dysfunction or loss and characterized by either LV dilation or hypertrophy or both. Whether the dysfunction is primarily systolic or diastolic or mixed, it leads to neurohormonal and circulatory abnormalities, usually resulting in characteristic symptoms such as fluid retention, shortness of breath, and fatigue, especially on exertion. In the absence of appropriate therapeutic intervention, HF is usually progressive at the level of both cardiac function and clinical symptoms. The severity of clinical symptoms may vary substantially during the course of the disease process and may not correlate with changes in underlying cardiac function. Although HF is progressive and often fatal, patients can be stabilized and myocardial dysfunction and remodeling may improve, either spontaneously or as a consequence of therapy. In physiologic terms, HF is a syndrome characterized by either or both pulmonary and systemic venous congestion and/or inadequate peripheral oxygen delivery, at rest or during stress, caused by cardiac dysfunction.

Additional Definitions 

HF is often classified as HF with reduced systolic function versus HF with preserved systolic function. Myocardial remodeling often precedes the clinical syndrome of HF. Additional definitions are provided in Table 2.1.

Table 2.1. Additional HF Definitions

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Section 3: Prevention of Ventricular Remodeling, Cardiac Dysfunction, and Heart Failure 

HF is an all-too-frequent outcome of hypertension and arterial vascular disease, making it a major public health concern.¹¹, ¹² Epidemiologic, clinical, and basic research have identified a number of antecedent conditions that predispose individuals to HF and its predecessors, LV remodeling and dysfunction.¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹ Recognition that many of these risk factors can be modified and that treating HF is difficult and costly has focused attention on preventive strategies for HF.

Development of both systolic and diastolic dysfunction related to adverse ventricular remodeling may take years to produce significant ill effects.²², ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸ Although the precise mechanisms for the transition to symptomatic HF are not clear, many modifiable factors have been identified that predispose or aggravate the remodeling process and the development of cardiac dysfunction. Treatment of systemic hypertension, with or without LV hypertrophy, reduces the development of HF.⁸, ²⁹, ³⁰, ³¹, ³², ³³, ³⁴, ³⁵, ³⁶ Prevention of myocardial infarction (MI) in patients with atherosclerotic cardiovascular disease is a critical intervention, since occurrence of MI confers an 8- to 10-fold increased risk for subsequent HF.³⁰ Other modifiable risk factors include anemia, diabetes, hyperlipidemia, obesity, valvular abnormalities, alcohol, certain illicit drugs, some cardiotoxic medications, and diet.³⁷, ³⁸

Recommendations for Patients With Risk Factors for Ventricular Remodeling, Cardiac Dysfunction, and Heart Failure 

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Section 4. Evaluation of Patients for Ventricular Dysfunction and Heart Failure 

Patients undergoing evaluation for ventricular dysfunction and HF fall into 3 general groups: (1) patients at risk of developing HF, (2) patients suspected of having HF based on signs and symptoms or incidental evidence of abnormal cardiac structure or function, and (3) patients with established symptomatic HF.

Patients at Risk for Heart Failure 

Patients identified to be at risk for HF require aggressive management of modifiable risk factors as outlined in Section 3 of this guideline. Patients with risk factors may have undetected abnormalities of cardiac structure or function. In addition to risk factor reduction, these patients require careful assessment for the presence of symptoms of HF and, depending on their underlying risk, may warrant noninvasive evaluation of cardiac structure and function.

Recommendations for Evaluation of Patients at Risk for Heart Failure 

Patients Suspected of Having HF 

The evaluation of patients suspected of having HF focuses on interpretation of signs and symptoms that have led to the consideration of this diagnosis. Careful history and physical examination, combined with evaluation of cardiac structure and function, should be undertaken to determine the cause of symptoms and to evaluate the degree of underlying cardiac pathology.

Recommendations for Evaluation of Patients Suspected of Having HF 

Patients With Established HF 

The evaluation of patients with an established diagnosis of HF is undertaken to identify the etiology, assess symptom nature and severity, determine functional impairment, and establish a prognosis. Follow-up of patients with HF or cardiac dysfunction involves continuing reassessment of symptoms, functional capacity, prognosis, and therapeutic effectiveness.

Recommendations for the Evaluation of Patients With Established HF 

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Section 5: Management of Asymptomatic Patients With Reduced Left Ventricular Ejection Fraction 

LV remodeling and reduced LVEF should be distinguished from the syndrome of clinical HF. When LVEF is reduced (<40%), but there are no signs and symptoms of HF, the condition frequently is referred to as asymptomatic LV dysfunction (ALVD). It is important to distinguish between ALVD and patients categorized as NYHA Class I HF. Although patients with NYHA Class I HF do not currently have HF symptoms, they may have ALVD currently, or they may have clinical systolic HF with symptoms in the past. In contrast, patients with ALVD have no past history of HF symptoms. It is now well recognized that there may be a latency period when the LVEF is reduced before the development of symptomatic HF. Although most attention in the HF literature has centered on patients with symptoms, evidence now indicates that ALVD is more common than previously assumed. The recent realization that therapies aimed at symptomatic HF may improve outcomes in patients with ALVD has increased the importance of recognizing and treating patients with this condition.

The management of patients with ALVD focuses on controlling cardiovascular risk factors and on the prevention or reduction of progressive ventricular remodeling. Exercise, smoking cessation, hypertension control, as well as treatment with ACE inhibitors (or ARBs) and beta blockers, all have a potential role in the treatment of this syndrome.

Recommendations for the Management of Asymptomatic Patients With Reduced LVEF 

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Section 6: Nonpharmacologic Management and Health Care Maintenance in Patients With Chronic Heart Failure 

Nonpharmacologic management strategies represent an important contribution to HF therapy. They may significantly impact patient stability, functional capacity, mortality, and quality of life. These strategies include diet and nutrition, oxygen supplementation, and management of concomitant conditions such as sleep apnea, insomnia, depression, and sexual dysfunction. Exercise training may also play a role in appropriate patients. Attention should be focused on the appropriate management of routine health maintenance issues.

Recommendations for Diet and Nutrition 

Recommendations for Other Therapies 

Recommendations for Specific Activity and Lifestyle Issues 

Recommendations for Routine Health Care Maintenance 

Recommendations for Exercise Testing/Exercise Training 

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Section 7: Heart Failure in Patients With Reduced Ejection Fraction 

There are 3 primary issues that must be considered when treating HF patients with reduced LVEF: (1) improving symptoms and quality of life, (2) slowing the progression or reversing cardiac and peripheral dysfunction, and (3) reducing mortality. General measures, such as salt restriction, weight loss, lipid control, and other nonpharmacologic measures are addressed in Section 6. Pharmacologic approaches to symptom control, including diuretics, vasodilators, intravenous inotropic drugs, anticoagulants, and antiplatelet agents are discussed at the end of this section.

Two classes of agents have become the recommended cornerstone of therapy to delay or halt progression of cardiac dysfunction and improve mortality: ACE inhibitors and beta blockers. Even while these agents are underused in the treatment of HF, new classes of agents have been added that show an impact on mortality, complicating decisions about optimal pharmacologic therapy. These include ARBs, aldosterone antagonists, and the combination of hydralazine and an oral nitrate (Table 7.1).

Table 7.1. ACE-inhibitor, Angiotensin Receptor Blocker, and Beta-Blocker Therapy in Heart Failure with Low Ejection Fraction

Recommendations for ACE-inhibitors 

There is compelling evidence that ACE inhibitors should be used to inhibit the renin-angiotensin-aldosterone system (RAAS) in all HF patients with reduced LVEF, whether or not they are symptomatic (Table 7.1). A number of large clinical trials have demonstrated improvement in morbidity and mortality in HF patients with reduced LVEF, both chronically and post-MI.⁴⁰, ⁴¹, ⁴²

Recommendations for Alternatives to ACE-inhibitors 

ACE inhibitors can have some troublesome side effects, including cough and angioedema, which may limit therapy with these agents. ARBs have been demonstrated to be well tolerated in randomized trials of patients judged to be intolerant of ACE inhibitors.⁴³, ⁴⁴ Both drugs have similar effects on blood pressure, renal function, and potassium.⁴³ Thus, patients intolerant of ACE-inhibitors for these reasons may also be intolerant of ARBs, and the combination of hydralazine and oral nitrates should be considered for these patients.

Recommendations for Angiotensin Receptor Blockers 

Both ACE inhibitors and ARBs inhibit the RAAS, but by different mechanisms. ACE inhibitors block an enzyme responsible for converting angiotensin I to angiotensin II and for degrading various kinins. However, during chronic therapy, angiotensin II levels are not completely suppressed by ACE inhibitors. ARBs block the effects of angiotensin II on the ATI receptor, independent of the source of angiotensin II production. ARBs have been compared to ACE-inhibitors in several clinical trials, in both chronic HF and in post-MI HF populations.

Recommendations for Beta Adrenergic Receptor Blockers 

Beta blocker therapy, advocated for HF by some investigators since the 1970s, remains a major advance in the treatment of patients with HF and reduced LVEF. Several large-scale clinical trials, involving more than 10,000 patients, have provided unequivocal evidence of important reductions in both mortality and morbidity.⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸, ⁴⁹, ⁵⁰, ⁵¹ The marked beneficial effects of beta blockade has been well demonstrated in large-scale clinical trials of symptomatic patients with NYHA class II-IV HF and reduced LVEF using carvedilol, bisoprolol, and metoprolol controlled release/extended release (CR/XL). ⁴⁷, ⁴⁸, ⁴⁹, ⁵⁰, ⁵¹ These trials added beta blockade to background therapy that included ACE inhibitors and diuretics in more than 90% of patients. The trial results support benefit from both beta₁ selective and nonselective beta blockers, whether ancillary properties are present or not. beta blocking agents with intrinsic sympathomimetic activity are likely to worsen survival and should be avoided in patients with HF.⁵² The beta-blockers studied in clinical trials are now established as routine therapy in patients with reduced LVEF. This therapy is well tolerated by a large majority of patients with HF, even those with comorbid conditions like diabetes mellitus,⁵³, ⁵⁴ chronic obstructive lung disease,⁵⁵ and peripheral vascular disease.⁵⁶

Recommendations for Combination ACE-inhibitor, ARB, and Beta Adrenergic Receptor Blocker Therapy 

Recommendations for Aldosterone Antagonists 

Sustained activation of aldosterone appears to play an important role in the pathophysiology of HF.⁵⁷ Although ACE inhibition may transiently decrease aldosterone secretion, there are diverse stimuli other than angiotensin II for the production of this hormone.⁵⁸ Studies suggest a rapid return of aldosterone to levels similar to those before ACE inhibition.⁵⁹ Aldosterone antagonists have demonstrated efficacy in both severe HF and in post-MI HF.⁶⁰, ⁶¹ Hyperkalemia is a serious adverse effect associated with both non-selective (i.e. spironolactone) and selective (i.e. eplerenone) aldosterone antagonists. In addition to hyperkalemia, gynecomastia or breast pain may be important side effects of spironolactone, but not eplerenone.

Recommendations for Oral Nitrates and Hydralazine 

The combination of hydralazine and isosorbide dinitrate has shown efficacy in several trials and plays a role in HF therapy as an alternative to ACE-inhibitors. Based on the results of the African American Heart Failure Trial (A-HeFT), it also is part of standard HF therapy in African Americans with HF and reduced LVEF.

Recommendations for Optimal Use of Multi-Drug Therapy 

Multi-drug therapy is required for optimal management to slow progression and improve outcome in patients with HF and reduced LVEF. An ACE inhibitor plus a beta blocker is standard background therapy. An ARB can be substituted for an ACE inhibitor if clinically indicated. An ARB can be added to an ACE inhibitor in individuals in whom beta blocker is contraindicated or not tolerated. The optimal choice of additional drug therapy to further improve outcome in patients already treated with 2 of these 3 drugs is not firmly established. An aldosterone inhibitor, an ARB (if the patient is already on an ACE inhibitor) and the combination of isosorbide dinitrate and hydralazine have all been shown to exert further benefit in controlled trials, but have not been the subject of comparative trials. The choice among these agents may be influenced by the patient's age, renal function, serum potassium, racial background, and severity of the clinical syndrome. Certain combinations require careful monitoring.

Recommendations for Diuretic Therapy 

Loop and distal tubular diuretics are necessary adjuncts in the medical therapy for HF when symptoms are the result of sodium and water retention. Diuretics reduce congestive symptoms and signs and can be titrated as needed to restore euvolemia and to reach an estimated “dry” weight goal for the patient. Relief of signs and symptoms must be achieved without causing side effects, particularly symptomatic hypotension or worsening renal function.

Recommendations for Digoxin 

Data from the Digitalis Investigation Group (DIG) trial and the combined databases of several other large trials provide evidence of digoxin's efficacy.⁶², ⁶³, ⁶⁴, ⁶⁵, ⁶⁶, ⁶⁷, ⁶⁸ Digoxin is a drug that is inexpensive and can be given once daily, and it continues to have a therapeutic role in symptomatic patients with HF from reduced LVEF.

Recommendations for Anticoagulation and Antiplatelet Drugs 

Patients with HF are recognized to be at increased risk for arterial or venous thromboembolic events. In addition to atrial fibrillation and poor ventricular function, which promote stasis and increase the risk of thrombus formation, patients with HF have other manifestations of hypercoagulability. Evidence of heightened platelet activation, increased plasma and blood viscosity, and increased plasma levels of fibrinopeptide A, beta—thromboglobulin, D-dimer, and von Willebrand factor have been found in many patients.⁶⁹, ⁷⁰, ⁷¹ Despite a predisposition, estimates regarding the incidence of thromboemboli in patients with HF vary substantially between 1.4% and 4.2% per 100 patient years.⁷², ⁷³, ⁷⁴ Although variability in the reported incidence likely results from differences in the populations studied and the methodology used to identify these events, the consensus is that pulmonary and systemic emboli are not common in HF patients in sinus rhythm. Traditionally, discussion of anticoagulation in patients with HF has centered on warfarin. Antiplatelet agents are often used in patients with HF from ischemic heart disease.

Recommendations for Amiodarone Therapy 

Ventricular arrhythmias are common in HF patients, and sudden cardiac death (SCD) continues to account for a significant proportion of the mortality in this syndrome. Many antiarrhythmic drugs have adverse hemodynamic effects sufficient to have negative consequences in patients with HF. Patients with HF are at higher risk for proarrhythmic effects of antiarrhythmic agents. The major role for the use of these agents in HF is to reduce recurrences of symptomatic arrhythmias, usually in patients who have an ICD.⁷⁵

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Section 8: Disease Management, Advance Directives, and End-of-Life Care in Heart Failure 

The majority of HF care is performed at home by the patient and family or caregiver. If these individuals do not know what is required, fail to see its importance, or face barriers to engagement in self-care, they will not participate effectively. For this reason, comprehensive education and counseling are the foundation for all HF management. The goals of education and counseling are to help patients, their families, and caregivers acquire the knowledge, skills, strategies, problem solving abilities, and motivation necessary for adherence to the treatment plan and effective participation in self-care. The inclusion of family members and other caregivers is especially important, because HF patients often suffer from cognitive impairment, functional disabilities, multiple comorbidities and other conditions that limit their ability to fully comprehend, appreciate, or enact what they learn.⁷⁶, ⁷⁷, ⁷⁸, ⁷⁹, ⁸⁰, ⁸¹, ⁸²

Recommendations for Education and Counseling 

Recommendations for Disease Management Programs 

Practitioners who care for patients with HF are challenged daily with preventing common, recurrent rehospitalizations for exacerbations. Disease management is "a comprehensive, integrated system for managing patients…by using best practices, clinical practice improvement…and other resources and tools to reduce overall cost and improve measurable outcomes in the quality of care.”⁸³ A number of disease management programs have been studied, including HF clinics,⁸⁴, ⁸⁵, ⁸⁶, ⁸⁷, ⁸⁸, ⁸⁹, ⁹⁰, ⁹¹, ⁹², ⁹³, ⁹⁴, ⁹⁵, ⁹⁶, ⁹⁷, ⁹⁸, ⁹⁹, ¹⁰⁰ care delivered in the home or to patients who are at home,¹⁰¹, ¹⁰², ¹⁰³, ¹⁰⁴, ¹⁰⁵, ¹⁰⁶, ¹⁰⁷, ¹⁰⁸, ¹⁰⁹, ¹¹⁰, ¹¹¹, ¹¹², ¹¹³, ¹¹⁴, ¹¹⁵, ¹¹⁶, ¹¹⁷ and telemonitoring.¹¹⁸, ¹¹⁹, ¹²⁰, ¹²¹, ¹²², ¹²³, ¹²⁴ These programs focus on multiple aspect of patient care, including optimization of drug therapy, patient and family/caregiver education and counseling, emphasis on self-care, vigilant follow-up, early attention to signs and symptoms of fluid overload, coordination of care with other providers, quality assessment, and increased access to the health care provider.

Recommendations for Advance Directives and End-of-Life Care 

HF has a worse prognosis than many common cancers,¹²⁵ and premature death from progressive acute decompensated heart failure (ADHF) or SCD is frequent. Recent advances in HF treatment have resulted in substantial reductions in annual mortality from these modes of death. Nevertheless, the mortality rate in HF remains high, making advance directives and end-of-life care important issues for patients with this condition. Hospice services or other end-of-life care should only be implemented after full and appropriate application of evidence-based pharmacologic and cardiac device therapies, unless documentation of intolerance or contraindication to such treatments is present. For critically ill patients, clinicians should acknowledge to the patient and their family the potentially life-threatening nature of their condition, and supportive care for them should be implemented as indicated. In most cases, adequate time (weeks to months) must be given to allow medical therapies to exert a beneficial therapeutic effect. In addition, issues such as access to care, adherence to medications and other self care behaviors, and knowledge about HF must be addressed. End-of-life care most often includes continuing HF therapies, which may effectively ease symptoms and stabilize or improve quality of life. A discussion about HF course and prognosis should be conducted with all patients to the extent that they are willing to participate in such a conversation. Discussion of end-of-life care can occur when the patient has progressed to a state of severe, refractory HF.

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Section 9: Electrophysiology Testing and the Use of Devices in Heart Failure 

Device therapy has become an integral part of the treatment for HF. Appropriate patient selection in terms of HF characteristics, severity, and other comorbidities is a key consideration to ensure the optimal application of this therapy.

Recommendations for General Electrophysiology Testing 

Recommendations for Electrophysiology Testing and Evaluation of Syncope 

Recommendations for Prophylactic ICD Placement 

More than 80 percent of patients who experience a life-threatening ventricular tachyarrhythmia do not survive to benefit from an ICD. Thus, the concept of the ICD for primary prevention of SCD has received considerable attention. Several large trials have demonstrated efficacy of prophylactic ICDs in certain patient groups.¹³⁰, ¹³¹, ¹³², ¹³³, ¹³⁴, ¹³⁵

Recommendations for Biventricular Resynchronization Pacing 

The majority of patients with HF have interventricular conduction delay, and up to 30% to 50% have manifest bundle branch block caused by direct pathologic involvement of specialized conduction or by scarring of the myocardium.¹³⁶ CRT seeks to normalize depolarization to improve the efficiency of ventricular contraction and ventricular septal motion, decrease atrioventricular valve regurgitation, and increase diastolic filling time.¹³⁷

Recommendations for Dual Chamber Pacemakers 

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Section 10: Surgical Approaches to the Treatment of Heart Failure 

Despite advances in medical management of HF, there remain circumstances in which surgical procedures are the only or the best treatment option. These include heart transplantation and procedures that (1) repair the heart, (2) reshape it, or (3) replace all or part of heart function.

Recommendations for Surgical Approaches 

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Section 11: Evaluation and Management of Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction 

A substantial number of patients with HF have preserved LVEF, variably defined as an LVEF >40%, >45%, or >50%.¹³⁸, ¹³⁹ When these patients have invasive or non-invasive evidence of abnormal diastolic function (either abnormal relaxation, filling or stiffness) they are said to have “diastolic HF”.¹⁴⁰ Although the term “HF with normal LVEF” is often used to denote this group, because “normal” is variously defined, “HF with preserved LVEF” will be the active definition in this document. The left ventricle in HF with preserved LVEF may be characterized by LV hypertrophy,¹⁴¹ concentric remodeling, increased extracellular matrix,¹⁴² abnormal calcium handling, abnormal relaxation and filling and decreased diastolic distensibility.¹⁴³, ¹⁴⁴ Activation of the neurohormonal milieu, including the RAAS and the sympathetic nervous system, is common in HF with and without preserved LVEF.¹⁴⁴

Recommendations for Patients With Heart Failure and Preserved LVEF 

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Section 12: Evaluation and Management of Patients With Acute Decompensated Heart Failure 

Data from several studies have refined our understanding of the clinical characteristics of patients hospitalized with worsening HF.¹⁴⁵, ¹⁴⁶, ¹⁴⁷, ¹⁴⁸ These studies demonstrate that the majority of patients hospitalized with HF have evidence of systemic hypertension on admission and commonly have preserved LVEF. Most hospitalized patients have significant volume overload, and congestive symptoms predominate. Patients with severely impaired systolic function, reduced blood pressure, and symptoms from poor end-organ perfusion are in the distinct minority. Natural history studies have shown that ADHF represents a period of high risk for patients, during which their likelihood of death and rehospitalization is significantly greater than for a comparable period of chronic, but stable HF.¹⁴⁶

The clinical classification of patients with ADHF continues to evolve and reflects ongoing changes in our understanding of the pathophysiology of this syndrome.¹⁴⁹ Worsening renal function, persistent neurohormonal activation, and progressive deterioration in myocardial function all seem to play a role. Decompensation also commonly occurs without a fundamental worsening of underlying cardiac structure or function. Failure to adhere to prescribed medications related to inadequate financial resources, poor compliance, and lack of education or an inadequate medical regimen may lead to hospitalization without a worsening of underlying circulatory function.

There is a paucity of controlled clinical trial data to define optimal treatment for patients with ADHF. The few trials have focused primarily on symptom relief, not outcomes, and have mainly enrolled patients with reduced LVEF who were not hypertensive. Clinical studies to determine the best care processes to achieve the multiple goals for patients admitted with ADHF are lacking. The recommendations in this section address the common therapeutic dilemmas associated with the broad group of patients with ADHF using the best available evidence from clinical research and consensus expert opinion.

Recommendations for Acute Decompensated Heart Failure 

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Section 13: Evaluation and Therapy for Heart Failure in the Setting of Ischemic Heart Disease 

The most common cause of chronic HF is no longer hypertension or valvular heart disease; it is CAD.² The changing pattern in the risk factors for HF is evidenced in the Framingham Heart Study, which documents a decrease in valvular disease and LV hypertrophy and an increase in MI from 1950 to 1998.³ As survival from MI continues to improve, it is expected that the number of patients with CAD and HF will also increase.

HF in the setting of CAD is a heterogeneous condition with several factors contributing to LV systolic dysfunction and HF symptoms. After an MI, there is loss of functioning myocytes, development of myocardial fibrosis, and subsequent LV remodeling, resulting in chamber dilatation and neurohormonal activation - all leading to progressive dysfunction of the remaining viable myocardium.⁴⁹

Several studies have shown that CAD is associated with an increase in mortality rates in patients with HF.³⁰, ³¹, ³², ³³, ³⁴, ³⁵, ³⁶ Data also suggest that the mechanism of sudden death may differ between ischemic and nonischemic HF patients, with acute coronary events representing the major cause of sudden death in HF patients with CAD.³⁸ These findings further emphasize the importance of accurate differentiation between ischemic and nonischemic causes of HF.

Managing HF in patients with CAD or a history of CAD may be significantly different than managing HF due to primary cardiomyopathy. Antiplatelet agents, smoking cessation, and lipid-lowering therapy are particularly important interventions in patients with HF due to CAD.⁴⁰ Trials of milrinone,⁴¹ amiodarone,¹⁸ amlodipine,¹⁵ and digoxin suggest that patients with HF in the setting of CAD may have a less favorable outcome than patients with HF from primary cardiomyopathy. Revascularization in highly selected patients with reduced LVEF and significant CAD, particularly those with anginal symptoms, may be associated with improved survival and may be considered in addition to risk modification.³³, ⁴², ⁴³, ⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸, ⁴⁹

Recommendations for Heart Failure in the Setting of Ischemic Heart Disease 

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Section 14: Managing Patients With Hypertension and Heart Failure 

Blood pressure is a simple measurement that assesses the interaction of heart function with vascular impedance. When heart function is normal, the impedance is the main determinant of blood pressure. Therefore, pressure (systolic and mean) becomes a powerful risk factor for development of LV hypertrophy, increased myocardial oxygen consumption, coronary atherosclerosis, and subsequent HF.¹⁵⁰, ¹⁵¹ Control of blood pressure in this setting is critical to prevent the development and progression of LV dysfunction.¹⁵²

When LV function is impaired, however, the relationship between impedance and cardiac function becomes more complex. Increases of impedance may impair LV emptying and thus not be reflected in a higher pressure. Under those circumstances therapy is aimed at the impedance, not at the blood pressure. Indeed, blood pressure may rise in response to effective therapy that improves LV emptying or reverses remodeling even if the impedance is reduced.

Recommendation for Patients With Hypertension and Preserved LVEF and Asymptomatic LVH, or for Patients With Hypertension and HF With Preserved LVEF (Stage B) 

Recommendations for Patients With Hypertension and Asymptomatic LV Dysfunction With LV Dilation and a Low LVEF 

Recommendations for Patients With Hypertension and Symptomatic LV Dysfunction With LV Dilation and Low LVEF 

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Section 15: Management of Heart Failure in Special Populations 

HF is a prevalent condition in women, African Americans, and the elderly of both sexes and any race. In the absence of contradictory data, the clinical recommendations based on trial data derived from predominately younger white male study populations have generally been applied equally to these groups. However, there are etiologic and pathophysiologic considerations specific to these groups that warrant attention if care and outcomes are to be optimized. Although a significant number of women and elderly patients with HF have preserved LV systolic function there is little evidence-based data to guide therapy in this group. Other special populations - ethnic groups such as Hispanics, Asians, American Indians, or Pacific Islanders - are important special populations but there are inadequate data currently available about HF management to discuss these groups individually. Discussion in this section is based primarily on available data from subgroup analyses of randomized HF trials and the results of cohort studies. A substantial amount of the data on drug efficacy comes from studies of patients treated after a recent acute MI.

Recommendations 

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Section 16: Myocarditis: Current Treatment 

Myocarditis is a distinct clinical entity with a wide variety of cardiac manifestations including HF. Potential etiologies may include toxins, medications, physical agents and, most importantly, infections. The most common forms appear to be postviral in origin. The pathophysiology of myocarditis has been well established in animal models with myocardial damage due not only to direct infection, but also consequent to postinfectious, autoimmune-mediated myocardial inflammatory damage. In humans, ongoing myocardial inflammation may result in dilated cardiomyopathy, restrictive cardiomyopathy, or acute LV failure without dilatation (fulminant myocarditis). Controversy continues to surround the best approach to the management of patients considered to have myocarditis. The following recommendation is based on a review of available data from uncontrolled and controlled evaluations of immunomodulatory therapy for the treatment of myocarditis.

Recommendations 

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Section 17: Genetic Evaluation of Cardiomyopathy^∗ 

The evidence indicating that hypertrophic cardiomyopathy (HCM) has a genetic basis is extensive: HCM is now understood largely to be a genetic disease of contractile proteins, although less commonly, infiltrative etiologies may also be causative. The evidence supporting a genetic basis for dilated cardiomyopathy (DCM), after other more common causes have been excluded (eg, ischemic disease, hypothyroidism, cardiotoxic agents such as Adriamycin), is now substantial for familial dilated cardiomyopathy (FDC), where FDC is defined as DCM of unknown cause in 2 or more closely related family members. However, whether sporadic DCM has a genetic basis remains an open question, especially when detectable familial disease has been clinically excluded by testing closely related family members. Thus, although some recommendations formulated for the genetic evaluation of cardiomyopathy, such as the need for family history, apply to all entities, other recommendations must be tailored to account for these differences. This is particularly relevant as these guidelines use the generic term “cardiomyopathy” to imply possible familial or genetic cause, assuming that all other detectable causes of cardiomyopathy have been ruled out. This is particularly relevant for DCM where multiple nongenetic causes are possible as noted previously. Recent discoveries indicate that arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is largely caused by mutations in genes encoding proteins of the desmosome. Although initially recognized predominantly in the right ventricle, LV involvement in 20% to 40% of patients has prompted the change in nomenclature from ARVD to ARVD/C.¹⁵³ Discovering the genetic basis of restrictive cardiomyopathy (RCM) has been more challenging, because RCM is much less common than DCM or HCM, and less commonly presents with familial disease. Left ventricular noncompaction (LVNC) is an anatomic abnormality of LV myocardial development: LV compaction is incomplete, leaving deep trabeculations in the LV myocardium. LVNC was categorized as a specific type of cardiomyopathy by an expert panel in 2006,¹⁵⁴ and some genetic association has been observed. Although initially reported to be a rare condition associated with adverse outcome,¹⁵⁵ more recent reports¹⁵⁶, ¹⁵⁷, ¹⁵⁸ have called into question those preliminary conclusions.¹⁵⁹ Three different echocardiographic criteria have been used for diagnosis.¹⁵⁶ These authors suggested that the diagnostic criteria for LVNC might be too sensitive. Because of the uncertainty of diagnostic standards leading to difficulty clarifying its phenotype, we suggest that the LVNC recommendations in this document be limited to those individuals with only the most prominent disease.

Recommendations for the Genetic Evaluation of Cardiomyopathy 

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Acknowledgment 

The Guideline Committee would like to thank the Executive Council for their review and comments and the following individuals for their input in revising specific sections; Jonathan G. Howlett (University of Calgary) and Richard J. Rodeheffer (Mayo Clinic & Foundation), Prevention Section; Marvin W. Kronenberg (Vanderbilt University), Nonpharmacologic Management and HF with Preserved LVEF Sections; Alan B. Miller (University of Florida, Jacksonville), Drug Therapy Section; Sarah J. Goodlin (Patient Centered Research and Education, Salt Lake City, Utah), Disease Management, Advance Directives, and End-of-Life Care in Heart Failure Section; Kenneth L. Baughman (deceased, Brigham & Women's Hospital, Boston, Massachusetts), Myocarditis Section; Michael R. Zile, MD, HF With Preserved LVEF Section; Bart Galle, PhD and Wendy Gattis Stough, PharmD for their scientific and editorial contributions; and Cheryl Yano for administrative support.

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Disclosures 

See Appendix C.

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Appendix A. 

Comparison of the 2006 and 2010 HFSA Guideline

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Appendix B. 

Acronyms

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Appendix C. 

Financial Disclosure

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References 

1. Adams K, Baughman K, Dec W, Elkayam U, Forker A, Gheorghiade M, et al. Heart Failure Society of America (HFSA) practice guidelines. HFSA guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction–pharmacological approaches. J Card Fail. 1999;5:357–382
   • View In Article
   • Full-Text PDF (2817 KB)
   • CrossRef
2. Adams K, Lindenfeld J, Arnold J, Baker D, Barnard D, Baughman K, et al. HFSA 2006 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2006;12:e1–e122
   • View In Article
3. Hershberger RE, Lindenfeld J, Mestroni L, Seidman CE, Taylor MR, Towbin JA. Genetic evaluation of cardiomyopathy–a Heart Failure Society of America practice guideline. J Card Fail. 2009;15:83–97
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (246 KB)
   • CrossRef
4. Fang J, Mensah GA, Croft JB, Keenan NL. Heart failure-related hospitalization in the U.S., 1979 to 2004. J Am Coll Cardiol. 2008;52:428–434
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (224 KB)
   • CrossRef
5. Koelling TM, Chen RS, Lubwama RN, L'Italien GJ, Eagle KA. The expanding national burden of heart failure in the United States: the influence of heart failure in women. Am Heart J. 2004;147:74–78
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (112 KB)
   • CrossRef
6. Loehr LR, Rosamond WD, Chang PP, Folsom AR, Chambless LE. Heart failure incidence and survival (from the Atherosclerosis Risk in Communities study). Am J Cardiol. 2008;101:1016–1022
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (176 KB)
   • CrossRef
7. McCullough PA, Philbin EF, Spertus JA, Kaatz S, Sandberg KR, Weaver WD. Confirmation of a heart failure epidemic: findings from the Resource Utilization Among Congestive Heart Failure (REACH) study. J Am Coll Cardiol. 2002;39:60–69
   • View In Article
   • Full-Text PDF (144 KB)
   • CrossRef
8. Baker DW. Prevention of heart failure. J Card Fail. 2002;8:333–346
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (85 KB)
   • CrossRef
9. Dunlay SM, Weston SA, Jacobsen SJ, Roger VL. Risk factors for heart failure: a population-based case-control study. Am J Med. 2009;122:1023–1028
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (200 KB)
   • CrossRef
10. Lee DS, Gona P, Vasan RS, Larson MG, Benjamin EJ, Wang TJ, et al. Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insights from the framingham heart study of the national heart, lung, and blood institute. Circulation. 2009;119:3070–3077
    • View In Article
    • CrossRef
11. Centers for Disease Control and Prevention . Mortality from congestive heart failure–United States, 1980-1990. JAMA. 1994;271:813–814
    • View In Article
    • MEDLINE
12. Centers for Disease Control and Prevention . Changes in mortality from heart failure–United States, 1980-1995. JAMA. 1998;280:874–875
    • View In Article
    • MEDLINE
    • CrossRef
13. Fox KF, Cowie MR, Wood DA, Coats AJ, Gibbs JS, Underwood SR, et al. Coronary artery disease as the cause of incident heart failure in the population. Eur Heart J. 2001;22:228–236
    • View In Article
    • MEDLINE
    • CrossRef
14. Grundy SM, Balady GJ, Criqui MH, Fletcher G, Greenland P, Hiratzka LF, et al. Primary prevention of coronary heart disease: guidance from Framingham: a statement for healthcare professionals from the AHA Task Force on Risk Reduction. American Heart Association. Circulation. 1998;97:1876–1887
    • View In Article
    • MEDLINE
15. Hellermann JP, Jacobsen SJ, Reeder GS, Lopez-Jimenez F, Weston SA, Roger VL. Heart failure after myocardial infarction: prevalence of preserved left ventricular systolic function in the community. Am Heart J. 2003;145:742–748
    • View In Article
    • Abstract
    • Full-Text PDF (113 KB)
    • CrossRef
16. Howard BV. Blood pressure in 13 American Indian communities: the Strong Heart Study. Public Health Rep. 1996;111(Suppl. 2):47–48
    • View In Article
17. Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, et al. Obesity and the risk of heart failure. N Engl J Med. 2002;347:305–313
    • View In Article
    • CrossRef
18. Kjekshus J, Pedersen TR, Olsson AG, Faergeman O, Pyorala K. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail. 1997;3:249–254
    • View In Article
    • Abstract
    • Full-Text PDF (544 KB)
    • CrossRef
19. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure. JAMA. 1996;275:1557–1562
    • View In Article
    • MEDLINE
20. Lopes AA, Andrade J, Noblat AC, Silveira MA. Reduction in diastolic blood pressure and cardiovascular mortality in nondiabetic hypertensive patients. A reanalysis of the HOT study. Arq Bras Cardiol. 2001;77:132–137
    • View In Article
    • MEDLINE
21. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405–412
    • View In Article
    • MEDLINE
    • CrossRef
22. Kostis JB, Davis BR, Cutler J, Grimm RH, Berge KG, Cohen JD, et al. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group. JAMA. 1997;278:212–216
    • View In Article
    • MEDLINE
23. McDonagh TA, Morrison CE, Lawrence A, Ford I, Tunstall-Pedoe H, McMurray JJ, et al. Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet. 1997;350:829–833
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (73 KB)
    • CrossRef
24. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med. 1971;285:1441–1446
    • View In Article
    • MEDLINE
    • CrossRef
25. Mitchell GF, Pfeffer JM, Pfeffer MA. The transition to failure in the spontaneously hypertensive rat. Am J Hypertens. 1997;10:120S–126S
    • View In Article
    • MEDLINE
    • CrossRef
26. Moser M, Hebert PR. Prevention of disease progression, left ventricular hypertrophy and congestive heart failure in hypertension treatment trials. J Am Coll Cardiol. 1996;27:1214–1218
    • View In Article
    • Abstract
    • Full-Text PDF (494 KB)
    • CrossRef
27. Pearson TA, Blair SN, Daniels SR, Eckel RH, Fair JM, Fortmann SP, et al. AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation. 2002;106:388–391
    • View In Article
    • CrossRef
28. Pfeffer JM, Pfeffer MA, Fletcher P, Fishbein MC, Braunwald E. Favorable effects of therapy on cardiac performance in spontaneously hypertensive rats. Am J Physiol. 1982;242:H776–H784
    • View In Article
    • MEDLINE
29. Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412–419
    • View In Article
    • MEDLINE
    • CrossRef
30. Arnold JM, Yusuf S, Young J, Mathew J, Johnstone D, Avezum A, et al. Prevention of Heart Failure in Patients in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation. 2003;107:1284–1290
    • View In Article
    • CrossRef
31. Fagard RH, Staessen JA. Treatment of isolated systolic hypertension in the elderly: the Syst-Eur trial. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Clin Exp Hypertens. 1999;21:491–497
    • View In Article
    • MEDLINE
    • CrossRef
32. Hansson L. Recent intervention trials in hypertension initiated in Sweden–HOT, CAPPP and others. Hypertension Optimal Treatment Study. Captopril Prevention Project. Clin Exp Hypertens. 1999;21:507–515
    • View In Article
    • MEDLINE
    • CrossRef
33. Hawkins CM. Isolated Systolic Hypertension, Morbidity, and Mortality: The SHEP Experience. Am J Geriatr Cardiol. 1993;2:25–27
    • View In Article
34. Lauer MS, Anderson KM, Levy D. Influence of contemporary versus 30-year blood pressure levels on left ventricular mass and geometry: the Framingham Heart Study. J Am Coll Cardiol. 1991;18:1287–1294
    • View In Article
    • Abstract
    • Full-Text PDF (631 KB)
    • CrossRef
35. UK Prospective Diabetes Study Group . Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ. 1998;317:713–720
    • View In Article
    • MEDLINE
    • CrossRef
36. United Kingdom Prospective Diabetes Study Group . United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ. 1995;310:83–88
    • View In Article
    • MEDLINE
    • CrossRef
37. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med. 2001;161:996–1002
    • View In Article
    • MEDLINE
    • CrossRef
38. Djousse L, Driver JA, Gaziano JM. Relation between modifiable lifestyle factors and lifetime risk of heart failure. JAMA. 2009;302:394–400
    • View In Article
    • CrossRef
39. Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2007;116:1736–1754
    • View In Article
    • CrossRef
40. Packer M, Cohn J. Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Am J Cardiol. 1999;83:1A–38A
    • View In Article
    • Full-Text PDF (342 KB)
    • CrossRef
41. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429–1435
    • View In Article
    • MEDLINE
    • CrossRef
42. The SOLVD Investigators . Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302
    • View In Article
    • MEDLINE
    • CrossRef
43. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362:772–776
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (93 KB)
    • CrossRef
44. Stecker EC, Fendrick AM, Knight BP, Aaronson KD. Prophylactic pacemaker use to allow beta-blocker therapy in patients with chronic heart failure with bradycardia. Am Heart J. 2006;151:820–828
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (209 KB)
    • CrossRef
45. Heidenreich PA, Lee TT, Massie BM. Effect of beta-blockade on mortality in patients with heart failure: a meta-analysis of randomized clinical trials. J Am Coll Cardiol. 1997;30:27–34
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (207 KB)
    • CrossRef
46. Lechat P, Packer M, Chalon S, Cucherat M, Arab T, Boissel JP. Clinical effects of beta-adrenergic blockade in chronic heart failure: a meta-analysis of double-blind, placebo-controlled, randomized trials. Circulation. 1998;98:1184–1191
    • View In Article
    • MEDLINE
47. CIBIS II Investigators . The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9–13
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (80 KB)
    • CrossRef
48. MERIT-HF Investigators . Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001–2007
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (122 KB)
    • CrossRef
49. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349–1355
    • View In Article
    • MEDLINE
    • CrossRef
50. Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum H, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106:2194–2199
    • View In Article
    • CrossRef
51. Flather MD, Shibata MC, Coats AJ, van Veldhuisen DJ, Parkhomenko A, Borbola J, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:215–225
    • View In Article
    • MEDLINE
    • CrossRef
52. The Xamoterol in Severe Heart Failure Study Group . Xamoterol in severe heart failure. Lancet. 1990;336:1–6
    • View In Article
    • Abstract
    • CrossRef
53. Deedwania PC, Giles TD, Klibaner M, Ghali JK, Herlitz J, Hildebrandt P, et al. Efficacy, safety and tolerability of metoprolol CR/XL in patients with diabetes and chronic heart failure: experiences from MERIT-HF. Am Heart J. 2005;149:159–167
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (201 KB)
    • CrossRef
54. Nodari S, Metra M, Dei CA, Dei CL. Efficacy and tolerability of the long-term administration of carvedilol in patients with chronic heart failure with and without concomitant diabetes mellitus. Eur J Heart Fail. 2003;5:803–809
    • View In Article
    • MEDLINE
    • CrossRef
55. Le Jemtel TH, Padeletti M, Jelic S. Diagnostic and therapeutic challenges in patients with coexistent chronic obstructive pulmonary disease and chronic heart failure. J Am Coll Cardiol. 2007;49:171–180
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (477 KB)
    • CrossRef
56. Paravastu SC, Mendonca D, Da SA. Beta blockers for peripheral arterial disease. Cochrane Database Syst Rev. 2008;CD005508
    • View In Article
57. Dzau VJ, Colucci WS, Hollenberg NK, Williams GH. Relation of the renin-angiotensin-aldosterone system to clinical state in congestive heart failure. Circulation. 1981;63:645–651
    • View In Article
    • MEDLINE
    • CrossRef
58. Okubo S, Niimura F, Nishimura H, Takemoto F, Fogo A, Matsusaka T, et al. Angiotensin-independent mechanism for aldosterone synthesis during chronic extracellular fluid volume depletion. J Clin Invest. 1997;99:855–860
    • View In Article
59. Struthers AD. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in chronic heart failure. J Card Fail. 1996;2:47–54
    • View In Article
    • Abstract
    • Full-Text PDF (758 KB)
    • CrossRef
60. Pitt B, Zannad F, Remme WJ. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–717
    • View In Article
    • MEDLINE
    • CrossRef
61. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–1321
    • View In Article
    • CrossRef
62. Adams KF, Gheorghiade M, Uretsky BF, Patterson JH, Schwartz TA, Young JB. Clinical benefits of low serum digoxin concentrations in heart failure. J Am Coll Cardiol. 2002;39:946–953
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (220 KB)
    • CrossRef
63. Gheorghiade M, Hall VB, Jacobsen G, Alam M, Rosman H, Goldstein S. Effects of increasing maintenance dose of digoxin on left ventricular function and neurohormones in patients with chronic heart failure treated with diuretics and angiotensin-converting enzyme inhibitors. Circulation. 1995;92:1801–1807
    • View In Article
    • MEDLINE
64. Gheorghiade M, Pitt B. Digitalis Investigation Group (DIG) trial: a stimulus for further research. Am Heart J. 1997;134:3–12
    • View In Article
    • Full Text
    • Full-Text PDF (1120 KB)
    • CrossRef
65. Packer M, Gheorghiade M, Young JB, Costantini PJ, Adams KF, Cody RJ, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med. 1993;329:1–7
    • View In Article
    • MEDLINE
    • CrossRef
66. The Digitalis Investigation Group . The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525–533
    • View In Article
    • MEDLINE
    • CrossRef
67. Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, Jolly MK. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol. 1993;22:955–962
    • View In Article
    • Abstract
    • Full-Text PDF (1015 KB)
    • CrossRef
68. Young JB, Gheorghiade M, Uretsky BF, Patterson JH, Adams KF. Superiority of "triple" drug therapy in heart failure: insights from the PROVED and RADIANCE trials. Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin. Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme. J Am Coll Cardiol. 1998;32:686–692
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (131 KB)
    • CrossRef
69. Yamamoto K, Ikeda U, Furuhashi K, Irokawa M, Nakayama T, Shimada K. The coagulation system is activated in idiopathic cardiomyopathy. J Am Coll Cardiol. 1995;25:1634–1640
    • View In Article
    • Abstract
    • Full-Text PDF (653 KB)
    • CrossRef
70. Sbarouni E, Bradshaw A, Andreotti F, Tuddenham E, Oakley CM, Cleland JG. Relationship between hemostatic abnormalities and neuroendocrine activity in heart failure. Am Heart J. 1994;127:607–612
    • View In Article
    • MEDLINE
    • CrossRef
71. Jafri SM, Ozawa T, Mammen E, Levine TB, Johnson C, Goldstein S. Platelet function, thrombin and fibrinolytic activity in patients with heart failure. Eur Heart J. 1993;14:205–212
    • View In Article
    • MEDLINE
    • CrossRef
72. Kyrle PA, Korninger C, Gossinger H, Glogar D, Lechner K, Niessner H, et al. Prevention of arterial and pulmonary embolism by oral anticoagulants in patients with dilated cardiomyopathy. Thromb Haemost. 1985;54:521–523
    • View In Article
    • MEDLINE
73. Ciaccheri M, Castelli G, Cecchi F, Nannini M, Santoro G, Troiani V, et al. Lack of correlation between intracavitary thrombosis detected by cross sectional echocardiography and systemic emboli in patients with dilated cardiomyopathy. Br Heart J. 1989;62:26–29
    • View In Article
    • MEDLINE
    • CrossRef
74. Dunkman WB, Johnson GR, Carson PE, Bhat G, Farrell L, Cohn JN. Incidence of thromboembolic events in congestive heart failure. The V-HeFT VA Cooperative Studies Group. Circulation. 1993;87:VI94–101
    • View In Article
    • MEDLINE
75. Connolly SJ, Dorian P, Roberts RS, Gent M, Bailin S, Fain ES, et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial. JAMA. 2006;295:165–171
    • View In Article
    • CrossRef
76. Boyd KJ, Murray SA, Kendall M, Worth A, Frederick BT, Clausen H. Living with advanced heart failure: a prospective, community based study of patients and their carers. Eur J Heart Fail. 2004;6:585–591
    • View In Article
    • MEDLINE
77. Brostrom A, Stromberg A, Dahlstrom U, Fridlund B. Sleep difficulties, daytime sleepiness, and health-related quality of life in patients with chronic heart failure. J Cardiovasc Nurs. 2004;19:234–242
    • View In Article
    • MEDLINE
78. Clark JC, Lan VM. Heart failure patient learning needs after hospital discharge. Appl Nurs Res. 2004;17:150–157
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (70 KB)
    • CrossRef
79. Horowitz CR, Rein SB, Leventhal H. A story of maladies, misconceptions and mishaps: effective management of heart failure. Soc Sci Med. 2004;58:631–643
    • View In Article
    • MEDLINE
    • CrossRef
80. Martinez-Selles M, Garcia Robles JA, Munoz R, Serrano JA, Frades E, Dominguez MM, et al. Pharmacological treatment in patients with heart failure: patients knowledge and occurrence of polypharmacy, alternative medicine and immunizations. Eur J Heart Fail. 2004;6:219–226
    • View In Article
    • MEDLINE
    • CrossRef
81. Moser DK, Watkins JF. Conceptualizing self-care in heart failure: a life course model of patient characteristics. J Cardiovasc Nurs. 2008;23:205–218
    • View In Article
82. Rogers AE, Addington-Hall JM, Abery AJ, McCoy AS, Bulpitt C, Coats AJ, et al. Knowledge and communication difficulties for patients with chronic heart failure: qualitative study. BMJ. 2000;321:605–607
    • View In Article
    • MEDLINE
    • CrossRef
83. Bernard S. Disease management: a pharmaceutical industry perspective. Pharmaceutical Exec. 1995;16:48–50
    • View In Article
84. Fonarow GC, Stevenson LW, Walden JA, Livingston NA, Steimle AE, Hamilton MA, et al. Impact of a comprehensive heart failure management program on hospital readmission and functional status of patients with advanced heart failure. J Am Coll Cardiol. 1997;30:725–732
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (201 KB)
    • CrossRef
85. Azevedo A, Pimenta J, Dias P, Bettencourt P, Ferreira A, Cerqueira-Gomes M. Effect of a heart failure clinic on survival and hospital readmission in patients discharged from acute hospital care. Eur J Heart Fail. 2002;4:353–359
    • View In Article
    • MEDLINE
    • CrossRef
86. Cintron G, Bigas C, Linares E, Aranda JM, Hernandez E. Nurse practitioner role in a chronic congestive heart failure clinic: in-hospital time, costs, and patient satisfaction. Heart Lung. 1983;12:237–240
    • View In Article
    • MEDLINE
87. Cline CM, Israelsson BY, Willenheimer RB, Broms K, Erhardt LR. Cost effective management programme for heart failure reduces hospitalisation. Heart. 1998;80:442–446
    • View In Article
    • MEDLINE
88. Doughty RN, Wright SP, Pearl A, Walsh HJ, Muncaster S, Whalley GA, et al. Randomized, controlled trial of integrated heart failure management: The Auckland Heart Failure Management Study. Eur Heart J. 2002;23:139–146
    • View In Article
    • MEDLINE
    • CrossRef
89. Ekman I, Andersson B, Ehnfors M, Matejka G, Persson B, Fagerberg B. Feasibility of a nurse-monitored, outpatient-care programme for elderly patients with moderate-to-severe, chronic heart failure. Eur Heart J. 1998;19:1254–1260
    • View In Article
    • MEDLINE
    • CrossRef
90. Hanumanthu S, Butler J, Chomsky D, Davis S, Wilson JR. Effect of a heart failure program on hospitalization frequency and exercise tolerance. Circulation. 1997;96:2842–2848
    • View In Article
    • MEDLINE
91. Hershberger RE, Ni H, Nauman DJ, Burgess D, Toy W, Wise K, et al. Prospective evaluation of an outpatient heart failure management program. J Card Fail. 2001;7:64–74
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (69 KB)
    • CrossRef
92. Holst DP, Kaye D, Richardson M, Krum H, Prior D, Aggarwal A, et al. Improved outcomes from a comprehensive management system for heart failure. Eur J Heart Fail. 2001;3:619–625
    • View In Article
    • MEDLINE
    • CrossRef
93. Ledwidge M, Barry M, Cahill J, Ryan E, Maurer B, Ryder M, et al. Is multidisciplinary care of heart failure cost-beneficial when combined with optimal medical care?. Eur J Heart Fail. 2003;5:381–389
    • View In Article
    • MEDLINE
    • CrossRef
94. O'Connell AM, Crawford MH, Abrams J. Heart failure disease management in an indigent population. Am Heart J. 2001;141:254–258
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (86 KB)
    • CrossRef
95. Paul S. Impact of a nurse-managed heart failure clinic: a pilot study. Am J Crit Care. 2000;9:140–146
    • View In Article
    • MEDLINE
96. Smith LE, Fabbri SA, Pai R, Ferry D, Heywood JT. Symptomatic improvement and reduced hospitalization for patients attending a cardiomyopathy clinic. Clin Cardiol. 1997;20:949–954
    • View In Article
    • MEDLINE
    • CrossRef
97. Stromberg A, Martensson J, Fridlund B, Levin LA, Karlsson JE, Dahlstrom U. Nurse-led heart failure clinics improve survival and self-care behaviour in patients with heart failure: results from a prospective, randomised trial. Eur Heart J. 2003;24:1014–1023
    • View In Article
    • MEDLINE
    • CrossRef
98. Whellan DJ, Gaulden L, Gattis WA, Granger B, Russell SD, Blazing MA, et al. The benefit of implementing a heart failure disease management program. Arch Intern Med. 2001;161:2223–2228
    • View In Article
    • MEDLINE
    • CrossRef
99. Hebert KA, Horswell RL, Dy S, Key IJ, Butler MK, Cerise FP, et al. Mortality benefit of a comprehensive heart failure disease management program in indigent patients. Am Heart J. 2006;151:478–483
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (113 KB)
    • CrossRef
100. Jaarsma T, van der Wal MH, Lesman-Leegte I, Luttik ML, Hogenhuis J, Veeger NJ, et al. Effect of moderate or intensive disease management program on outcome in patients with heart failure: Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH). Arch Intern Med. 2008;168:316–324
     • View In Article
     • CrossRef
101. Krumholz HM, Amatruda J, Smith GL, Mattera JA, Roumanis SA, Radford MJ, et al. Randomized trial of an education and support intervention to prevent readmission of patients with heart failure. J Am Coll Cardiol. 2002;39:83–89
     • View In Article
     • Full-Text PDF (128 KB)
     • CrossRef
102. Naylor MD, Brooten D, Campbell R, Jacobsen BS, Mezey MD, Pauly MV, et al. Comprehensive discharge planning and home follow-up of hospitalized elders: a randomized clinical trial. JAMA. 1999;281:613–620
     • View In Article
     • MEDLINE
     • CrossRef
103. Riegel B, Carlson B, Glaser D, Hoagland P. Which patients with heart failure respond best to multidisciplinary disease management?. J Card Fail. 2000;6:290–299
     • View In Article
     • Abstract
     • Full-Text PDF (237 KB)
     • CrossRef
104. Riegel B, Carlson B, Kopp Z, LePetri B, Glaser D, Unger A. Effect of a standardized nurse case-management telephone intervention on resource use in patients with chronic heart failure. Arch Intern Med. 2002;162:705–712
     • View In Article
     • MEDLINE
     • CrossRef
105. Blue L, Lang E, McMurray JJ, Davie AP, McDonagh TA, Murdoch DR, et al. Randomised controlled trial of specialist nurse intervention in heart failure. BMJ. 2001;323:715–718
     • View In Article
     • MEDLINE
     • CrossRef
106. Jaarsma T, Halfens R, Huijer Abu-Saad H, Dracup K, Gorgels T, van RJ, et al. Effects of education and support on self-care and resource utilization in patients with heart failure. Eur Heart J. 1999;20:673–682
     • View In Article
     • MEDLINE
     • CrossRef
107. Kasper EK, Gerstenblith G, Hefter G, Van AE, Brinker JA, Thiemann DR, et al. A randomized trial of the efficacy of multidisciplinary care in heart failure outpatients at high risk of hospital readmission. J Am Coll Cardiol. 2002;39:471–480
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (114 KB)
     • CrossRef
108. Kornowski R, Zeeli D, Averbuch M, Finkelstein A, Schwartz D, Moshkovitz M, et al. Intensive home-care surveillance prevents hospitalization and improves morbidity rates among elderly patients with severe congestive heart failure. Am Heart J. 1995;129:762–766
     • View In Article
     • Abstract
     • Full-Text PDF (513 KB)
     • CrossRef
109. Rich MW, Vinson JM, Sperry JC, Shah AS, Spinner LR, Chung MK, et al. Prevention of readmission in elderly patients with congestive heart failure: results of a prospective, randomized pilot study. J Gen Intern Med. 1993;8:585–590
     • View In Article
     • MEDLINE
     • CrossRef
110. Rich MW, Beckham V, Wittenberg C, Leven CE, Freedland KE, Carney RM. Repetitive Hospital Admissions for Congestive Heart Failure in the Elderly. Am J Geriatr Cardiol. 1996;5:32–36
     • View In Article
111. Stewart S, Pearson S, Horowitz JD. Effects of a home-based intervention among patients with congestive heart failure discharged from acute hospital care. Arch Intern Med. 1998;158:1067–1072
     • View In Article
     • MEDLINE
     • CrossRef
112. Stewart S, Marley JE, Horowitz JD. Effects of a multidisciplinary, home-based intervention on unplanned readmissions and survival among patients with chronic congestive heart failure: a randomised controlled study. Lancet. 1999;354:1077–1083
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (92 KB)
     • CrossRef
113. Stewart S, Vandenbroek AJ, Pearson S, Horowitz JD. Prolonged beneficial effects of a home-based intervention on unplanned readmissions and mortality among patients with congestive heart failure. Arch Intern Med. 1999;159:257–261
     • View In Article
     • MEDLINE
     • CrossRef
114. Stewart S, Horowitz JD. Home-based intervention in congestive heart failure: long-term implications on readmission and survival. Circulation. 2002;105:2861–2866
     • View In Article
     • CrossRef
115. West JA, Miller NH, Parker KM, Senneca D, Ghandour G, Clark M, et al. A comprehensive management system for heart failure improves clinical outcomes and reduces medical resource utilization. Am J Cardiol. 1997;79:58–63
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (199 KB)
     • CrossRef
116. Tilney C, Whiting S, Horrar J, Perkins B, Vance R. Improved clinical and financial outcomes associated with a comprehensive congestive heart failure program. Disease Management. 1998;1:175–183
     • View In Article
117. Riegel B, Carlson B, Glaser D, Kopp Z, Romero TE. Standardized telephonic case management in a Hispanic heart failure population - An effective intervention. Disease Management & Health Outcomes. 2002;10:241–249
     • View In Article
118. Cordisco ME, Benjaminovitz A, Hammond K, Mancini D. Use of telemonitoring to decrease the rate of hospitalization in patients with severe congestive heart failure. Am J Cardiol. 1999;84:860–862A8
     • View In Article
     • Full Text
     • Full-Text PDF (86 KB)
     • CrossRef
119. de Lusignan S, Meredith K, Wells S, Leatham E, Johnson P. A controlled pilot study in the use of telemedicine in the community on the management of heart failure–a report of the first three months. Stud Health Technol Inform. 1999;64:126–137
     • View In Article
     • MEDLINE
120. de Lusignan S, Wells S, Johnson P, Meredith K, Leatham E. Compliance and effectiveness of 1 year's home telemonitoring. The report of a pilot study of patients with chronic heart failure. Eur J Heart Fail. 2001;3:723–730
     • View In Article
     • MEDLINE
     • CrossRef
121. Heidenreich PA, Ruggerio CM, Massie BM. Effect of a home monitoring system on hospitalization and resource use for patients with heart failure. Am Heart J. 1999;138:633–640
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (154 KB)
     • CrossRef
122. Jerant AF, Azari R, Nesbitt TS. Reducing the cost of frequent hospital admissions for congestive heart failure: a randomized trial of a home telecare intervention. Med Care. 2001;39:1234–1245
     • View In Article
     • MEDLINE
     • CrossRef
123. Shah NB, Der E, Ruggerio C, Heidenreich PA, Massie BM. Prevention of hospitalizations for heart failure with an interactive home monitoring program. Am Heart J. 1998;135:373–378
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (175 KB)
     • CrossRef
124. Benatar D, Bondmass M, Ghitelman J, Avitall B. Outcomes of chronic heart failure. Arch Intern Med. 2003;163:347–352
     • View In Article
     • MEDLINE
     • CrossRef
125. Stewart S, MacIntyre K, Hole DJ, Capewell S, McMurray JJ. More ‘malignant’ than cancer? Five-year survival following a first admission for heart failure. Eur J Heart Fail. 2001;3:315–322
     • View In Article
     • MEDLINE
     • CrossRef
126. Setoguchi S, Stevenson LW, Schneeweiss S. Repeated hospitalizations predict mortality in the community population with heart failure. Am Heart J. 2007;154:260–266
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (621 KB)
     • CrossRef
127. Solomon SD, Dobson J, Pocock S, Skali H, McMurray JJ, Granger CB, et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation. 2007;116:1482–1487
     • View In Article
     • CrossRef
128. Elkayam U, Tasissa G, Binanay C, Stevenson LW, Gheorghiade M, Warnica JW, et al. Use and impact of inotropes and vasodilator therapy in hospitalized patients with severe heart failure. Am Heart J. 2007;153:98–104
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (214 KB)
     • CrossRef
129. Stevenson LW, Miller LW, Desvigne-Nickens P, Ascheim DD, Parides MK, Renlund DG, et al. Left ventricular assist device as destination for patients undergoing intravenous inotropic therapy: a subset analysis from REMATCH (Randomized Evaluation of Mechanical Assistance in Treatment of Chronic Heart Failure). Circulation. 2004;110:975–981
     • View In Article
     • CrossRef
130. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352:225–237
     • View In Article
     • CrossRef
131. Bigger JT. Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. N Engl J Med. 1997;337:1569–1575
     • View In Article
     • MEDLINE
     • CrossRef
132. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De MT, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350:2140–2150
     • View In Article
     • CrossRef
133. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med. 1999;341:1882–1890
     • View In Article
     • MEDLINE
     • CrossRef
134. Buxton AE, Lee KL, Hafley GE, Wyse DG, Fisher JD, Lehmann MH, et al. Relation of ejection fraction and inducible ventricular tachycardia to mode of death in patients with coronary artery disease: an analysis of patients enrolled in the multicenter unsustained tachycardia trial. Circulation. 2002;106:2466–2472
     • View In Article
     • CrossRef
135. Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med. 1996;335:1933–1940
     • View In Article
     • MEDLINE
     • CrossRef
136. Cazeau S, Ritter P, Lazarus A, Gras D, Backdach H, Mundler O, et al. Multisite pacing for end-stage heart failure: early experience. Pacing Clin Electrophysiol. 1996;19:1748–1757
     • View In Article
     • MEDLINE
     • CrossRef
137. Leclercq C, Cazeau S, Le BH, Ritter P, Mabo P, Gras D, et al. Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure. J Am Coll Cardiol. 1998;32:1825–1831
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (152 KB)
     • CrossRef
138. Gaasch WH. Diagnosis and treatment of heart failure based on left ventricular systolic or diastolic dysfunction. JAMA. 1994;271:1276–1280
     • View In Article
     • MEDLINE
139. Smith GL, Masoudi FA, Vaccarino V, Radford MJ, Krumholz HM. Outcomes in heart failure patients with preserved ejection fraction: mortality, readmission, and functional decline. J Am Coll Cardiol. 2003;41:1510–1518
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (136 KB)
     • CrossRef
140. Swedberg K, Cleland J, Dargie H, Drexler H, Follath F, Komajda M, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J. 2005;26:1115–1140
     • View In Article
     • MEDLINE
     • CrossRef
141. Pearlman ES, Weber KT, Janicki JS, Pietra GG, Fishman AP. Muscle fiber orientation and connective tissue content in the hypertrophied human heart. Lab Invest. 1982;46:158–164
     • View In Article
     • MEDLINE
142. Huysman JA, Vliegen HW, Van der Laarse A, Eulderink F. Changes in nonmyocyte tissue composition associated with pressure overload of hypertrophic human hearts. Pathol Res Pract. 1989;184:577–581
     • View In Article
     • MEDLINE
     • CrossRef
143. Gwathmey JK, Copelas L, MacKinnon R, Schoen FJ, Feldman MD, Grossman W, et al. Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ Res. 1987;61:70–76
     • View In Article
     • MEDLINE
144. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: Part II: causal mechanisms and treatment. Circulation. 2002;105:1503–1508
     • View In Article
     • CrossRef
145. Adams KF, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2005;149:209–216
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (312 KB)
     • CrossRef
146. Blackledge HM, Tomlinson J, Squire IB. Prognosis for patients newly admitted to hospital with heart failure: survival trends in 12 220 index admissions in Leicestershire 1993-2001. Heart. 2003;89:615–620
     • View In Article
147. Krumholz HM, Parent EM, Tu N, Vaccarino V, Wang Y, Radford MJ, et al. Readmission after hospitalization for congestive heart failure among Medicare beneficiaries. Arch Intern Med. 1997;157:99–104
     • View In Article
     • MEDLINE
148. Lloyd-Jones D, Adams R, Carnethon M, De SG, Ferguson TB, Flegal K, et al. Heart Disease and Stroke Statistics–2009 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119:e21–e181
     • View In Article
     • CrossRef
149. Felker GM, Adams KF, Konstam MA, O'Connor CM, Gheorghiade M. The problem of decompensated heart failure: nomenclature, classification, and risk stratification. Am Heart J. 2003;145:S18–S25
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (91 KB)
     • CrossRef
150. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903–1913
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (146 KB)
     • CrossRef
151. Vasan RS, Larson MG, Leip EP, Evans JC, O'donnell CJ, Kannel WB, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med. 2001;345:1291–1297
     • View In Article
     • MEDLINE
     • CrossRef
152. Domanski MJ, Mitchell GF, Norman JE, Exner DV, Pitt B, Pfeffer MA. Independent prognostic information provided by sphygmomanometrically determined pulse pressure and mean arterial pressure in patients with left ventricular dysfunction. J Am Coll Cardiol. 1999;33:951–958
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (155 KB)
     • CrossRef
153. Sen-Chowdhry S, Syrris P, McKenna WJ. Role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol. 2007;50:1813–1821
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (251 KB)
     • CrossRef
154. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, et al. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation. 2006;113:1807–1816
     • View In Article
     • CrossRef
155. Chin TK, Perloff JK, Williams RG, Jue K, Mohrmann R. Isolated noncompaction of left ventricular myocardium. A study of eight cases. Circulation. 1990;82:507–513
     • View In Article
     • MEDLINE
     • CrossRef
156. Kohli SK, Pantazis AA, Shah JS, Adeyemi B, Jackson G, McKenna WJ, et al. Diagnosis of left-ventricular non-compaction in patients with left-ventricular systolic dysfunction: time for a reappraisal of diagnostic criteria?. Eur Heart J. 2008;29:89–95
     • View In Article
     • CrossRef
157. Murphy RT, Thaman R, Blanes JG, Ward D, Sevdalis E, Papra E, et al. Natural history and familial characteristics of isolated left ventricular non-compaction. Eur Heart J. 2005;26:187–192
     • View In Article
     • MEDLINE
     • CrossRef
158. Pignatelli RH, McMahon CJ, Dreyer WJ, Denfield SW, Price J, Belmont JW, et al. Clinical characterization of left ventricular noncompaction in children: a relatively common form of cardiomyopathy. Circulation. 2003;108:2672–2678
     • View In Article
     • CrossRef
159. Sen-Chowdhry S, McKenna WJ. Left ventricular noncompaction and cardiomyopathy: cause, contributor, or epiphenomenon?. Curr Opin Cardiol. 2008;23:171–175
     • View In Article
     • CrossRef
160. Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997;349:747–752
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (89 KB)
     • CrossRef
161. Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation. 1999;100:2312–2318
     • View In Article
     • MEDLINE
162. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362:759–766
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (128 KB)
     • CrossRef
163. Konstam MA, Neaton JD, Dickstein K, Drexler H, Komajda M, Martinez FA, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet. 2009;374:1840–1848
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (251 KB)
     • CrossRef
164. Cohn JN, Tognoni G. Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. New England Journal of Medicine. 2001;345:1667–1675
     • View In Article
165. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651–1658
     • View In Article
     • MEDLINE
     • CrossRef
166. Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R, Ferdinand K, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351:2049–2057
     • View In Article
     • CrossRef
167. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1986;314:1547–1552
     • View In Article
     • MEDLINE
     • CrossRef