Ebook The 4 stages of heart failure: Part 1

The 4 Stages of Heart Failure



The 4 Stages of Heart Failure

Brian E. Jaski, MD, FACC

Director of Clinical Research, San Diego Cardiac Center
Medical Director, Advanced Heart Failure and Cardiac Transplant
Sharp Memorial Hospital
San Diego, California

Minneapolis, Minnesota


© 2015 Brian E. Jaski
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ISBN: 978-1-935395-30-0
Printed in the United States of America


TABLE OF CONTENTS

In Gratitude . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
About the Author. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv
Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Chapter 1
HEART FAILURE DIAGNOSIS AND EPIDEMIOLOGY
Heart Failure Recognition . . . . . . . . . . . . . . . . .
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . .
Hospitalization Admissions and Readmission . . . . .
Heart Failure Mortality . . . . . . . . . . . . . . . . . .
Costs of Heart Failure . . . . . . . . . . . . . . . . . . .

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Chapter 2
HEART FAILURE PRESENTATIONS AND FUNCTIONAL TYPES.
Heart Failure Designation Based on Left
Ventricular Systolic Function . . . . . . . . . . . . . . . . . . . .
Acute and Chronic Presentations of Heart Failure . . . . . . . . .
Common Causes of Heart Failure . . . . . . . . . . . . . . . . . . .
Heart Failure Blunts Exercise Capacity . . . . . . . . . . . . . . . .
The Role of Biomarkers BNP and NT-proBNP
When Heart Failure Is Suspected . . . . . . . . . . . . . . . . .
Other Heart Failure Biomarkers . . . . . . . . . . . . . . . . . . . .
Chapter 3
STAGE A: PATIENTS AT RISK FOR DEVELOPING
STRUCTURAL HEART DISEASE . . . . . . . . . . . . . . . . . . .
Major Risk Factors and Increasing Prevalence of Heart Failure .
Treatable Risk Factors for Heart Failure . . . . . . . . . . . . . .
Goals for the Management of Heart Failure Risk Factors . . . .

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Chapter 4
STRUCTURAL HEART DISEASE AND PROGRESSION TO FAILURE:
STAGES B, C, AND D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Morphologic Changes in Heart Failure . . . . . . . . . . . . . . . . . . . 60
Patterns of Maladaptive Hypertrophy . . . . . . . . . . . . . . . . . . . . 62
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vi • Table of Contents

Neurohumoral Circulatory Responses . . . . . . . . . . . . . . . . . . . 65
Intracellular Mechanisms of Progression . . . . . . . . . . . . . . . . . . 68
Gene Mutations in Heart Failure. . . . . . . . . . . . . . . . . . . . . . . 74
Chapter 5
STAGE B: ASYMPTOMATIC STRUCTURAL HEART DISEASE
Who Is the Stage B Pre-Heart Failure Patient? . . . . . . . . .
Neurohumoral Continuum from Stage B
to Stage C Systolic Dysfunction . . . . . . . . . . . . . . . . .
The Continuum from Hypertension to HF-pEF . . . . . . . . .
Cardiac and Noncardiac Interactions . . . . . . . . . . . . . . .
Screening Tests for Stage B Heart Failure. . . . . . . . . . . . .
Management of Stage B Patients . . . . . . . . . . . . . . . . . .
Chapter 6

ASSESSMENT OF STAGE C PATIENTS WITH HF-rEF
The “3 Fs” of Ongoing Heart Failure Assessment . . .
Fit: Do Findings Fit the Diagnosis of Heart Failure?. .
Function: Is Left Ventricular Systolic Function
Abnormal by Echocardiography? . . . . . . . . . . .
Factors: What Are the Etiologies of Heart Failure? . .
Important Diagnostic Techniques for Heart Failure .

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Chapter 7
ASSESSMENT OF STAGE C PATIENTS WITH HF-pEF
Diagnosis of HF-pEF . . . . . . . . . . . . . . . . . . . .
Management of Hypertrophic Cardiomyopathy . . . .
Restrictive Cardiomyopathy Due to Amyloidosis . . .
Additional Causes of Restrictive Cardiomyopathy . .
Other Important Causes of Heart Failure Syndrome .
Valvular Heart Disease . . . . . . . . . . . . . . . . . .
Congenital Heart Disease . . . . . . . . . . . . . . . . .
Pericardial Disease . . . . . . . . . . . . . . . . . . . . .
Cor Pulmonale . . . . . . . . . . . . . . . . . . . . . . .
Sleep-Disordered Breathing in Heart Failure. . . . . .

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Chapter 8
STAGE C: IMPROVING OUTCOMES IN
SYMPTOMATIC HEART FAILURE . . . . . . . . . . .
Evidence-Based Therapies for Patients with HF-rEF
Volume Management with Diuretics . . . . . . . . .
Angiotensin II Inhibition . . . . . . . . . . . . . . . .
Beta Adrenoreceptor Blockade . . . . . . . . . . . . .
Mineralocorticoid Receptor Antagonists . . . . . . .
Neutral Endopeptidase Inhibition . . . . . . . . . . .
Nitrates and Hydralazine . . . . . . . . . . . . . . . .

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Table of Contents • vii

Digoxin . . . . . . . . . . . . . . . . . . . . .
Electrical Therapies for Heart Failure . . .
Atrial Fibrillation and Heart Failure . . . .
Treatment of HF-pEF. . . . . . . . . . . . .
Outpatient Hemodynamic Monitoring for
Congestion in HF-pEF and HF-rEF . . .

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Chapter 9
STAGE C: THERAPIES FOR ACUTE
DECOMPENSATED HEART FAILURE . . . . . . . . . . . . . . . .

Applying The “3 Fs” to Decompensated Heart Failure . . . . . . .
Hemodynamic Profiles in Decompensated Heart Failure . . . . .
Volume Management. . . . . . . . . . . . . . . . . . . . . . . . . . .
Intravenous Vasoactive Drug Therapy and Acute Heart Failure .
Comparative Hemodynamic Effects of Intravenous Medications .
Mechanical Circulatory Support . . . . . . . . . . . . . . . . . . .

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Chapter 10
STAGE C: CARDIORENAL SYNDROME . . . . . . . . . . . . . . .
The Cardiorenal Syndrome: Definition and Characteristics . . .
Measuring Renal Function . . . . . . . . . . . . . . . . . . . . . .
Association of Abnormal GFR and Heart Failure Mortality . . .
Factors Affecting GFR . . . . . . . . . . . . . . . . . . . . . . . . .
Management of Heart Failure with Impaired Kidney Function .

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Chapter 11
STAGE D HEART FAILURE: OPTIONS AND OPPORTUNITIES
Who Is the Stage D Heart Failure Patient? . . . . . . . . . . . . .
Palliative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cardiac Transplant . . . . . . . . . . . . . . . . . . . . . . . . . . .
Left Ventricular Assist Device (LVAD) . . . . . . . . . . . . . . .
Investigational Therapy . . . . . . . . . . . . . . . . . . . . . . . .

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Chapter 12
A PATIENT-ORIENTED PERSPECTIVE
TO THE 4 STAGES OF HEART FAILURE
Lifestyle Recommendations . . . . . . . . .
Outpatient Support and Monitoring . . .
Summary of Therapeutic Approaches
to the 4 Stages of Heart Failure . . . . .
Concluding Comments . . . . . . . . . . .

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Appendix A: Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
Appendix B: Summary of Clinical Trials of Therapy . . . . . . . . . . . 295

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307



IN GRATITUDE
I am deeply grateful to many individuals who helped make this guide
possible. I thank Dr. Sharon Hunt, who pioneered a paradigm of progressive stages of heart failure and Dr. Clyde Yancy, who advanced this
construct.  My present and past colleagues at the San Diego Cardiac
Center and Sharp Memorial Hospital have served as a source of encouragement, knowledge, and inspiration. Dr. Kirk Peterson reviewed a draft
of this book and provided wise counsel regarding both presentation and
content. I thank the Sharp Foundation for its support.
This publication benefited from the tireless efforts of my research
associates Bryan Ortiz, Christopher Grigoriadis, Jessica Alicdan, Justin
Gibson, and  Michelle Williamson. Their technical skills, insights, and
optimism have buoyed me throughout the 4-year  period of  concept to
product. I am indebted to the team at Cardiotext Publishing, especially
Dr. Katharine Swenson, who as a former cardiology fellow of mine and a
clinical cardiologist has been unique in her ability to edit and guide the
final phases of this project.
I gratefully acknowledge the cardiology fellows from Balboa Naval
Hospital.  Over the last 25 years, during their Heart Failure rotations at
Sharp Memorial hospital, I honed the principles and practices put forth
in this book, demonstrating the proverb “by learning you will teach; by
teaching you will learn.”
I dedicate this book to my patients whose courage, resilience, and
humility have served as both raison d’être and model for my professional
life.
Finally, to “my girls”—my wife Cindy and our daughter KC: The joy
you have brought to my life makes everything else possible.
—Brian E. Jaski, MD

San Diego Cardiac Center
January 2015

ix



ABOUT THE AUTHOR
Brian E. Jaski, MD, FACC, is a clinical cardiologist,
researcher, and medical educator. After earning
undergraduate degrees in electrical engineering and
biology from MIT, he graduated from Harvard
Medical School, Harvard-MIT Division of Health
Sciences Technology, where he subsequently also
completed a cardiology fellowship at the Brigham and
Women’s Hospital. Since 1985, when he joined the
San Diego Cardiac Center, he has served as Medical Director of the
Advanced Heart Failure and Cardiac Transplant program at Sharp
Memorial Hospital. He publishes in the areas of cardiac pathophysiology,
pharmacology, circulatory support devices, and cardiac transplant. He is
board certified in the subspecialties of Advanced Heart Failure and
Cardiac Transplant and Interventional Cardiology. He founded Heart
Failure Online (www.heartfailure.org) in 1996. He enjoys family, travel,
and running half marathons.

xi



FOREWORD

In my recent role as President of the World Heart Federation, I became
acutely aware and concerned that the world’s increasing and aging population, globalization, and rapid urbanization have fundamentally changed
disease patterns. Noncommunicable diseases, of which cardiovascular
disease accounts for nearly half, have overtaken communicable diseases
as leading causes of death and disability in the world. Cardiovascular
disease remains the number 1 global cause of death, accounting for 17.3
million deaths per year, a number that is expected to grow to 23.6 million
by 2030. As a Past President of the American Heart Association, I know
too well that in the United States, heart failure is a major cause of morbidity and mortality, and for more than a decade has been the leading
cause for hospital admissions in the Medicare population.
Significant advances have occurred in our understanding and management of heart failure. In particular, an expanded view of origins
ranging from environmental to genetic cardiovascular risk factors has
emerged. Once the stage is set for structural heart disease, the progression to more advanced heart failure may unfold gradually or rapidly.
Detailed guidelines have been published and widely distributed to
address the need for diagnosis and treatment of heart failure, and since
2010, Advanced Heart Failure and Cardiac Transplant has assumed subspecialty status within the American Board of Internal Medicine. But the
challenge remains when interpreting new guidelines in clinical situations:
when should recommendations be applied and for whom?
I first met, and subsequently recruited, Brian Jaski to join the San
Diego Cardiac Center when he was a third-year cardiology fellow at the
Brigham and Women’s Hospital. I was impressed by his background in
scientific principles, which he utilized in the practice of clinical cardiology, and by his strong clinical abilities and devotion to patient care. In the
thirty years since we first met, my respect for him has only grown.
In addition to developing a highly successful, internationally recognized advanced heart failure program in San Diego, Brian has participated
in and chaired data and safety monitoring and adverse event adjudication
committees for both drug and device multicenter trials. His many publications reflect the breadth of his knowledge and contributions.
After three decades of practice, research, and teaching, Brian’s
cumulative experience and clinical acumen is distilled and presented in
this book using the model of the 4 stages of heart failure as a backbone.
His book is unique in its single-author coordination, yet reflects Brian’s

multiple perspectives.
This book will be valuable to all training and practicing clinicians.
The latest therapies are detailed with practical tips for application. His
xiii


xiv • Foreword

book is beautifully color illustrated with summary diagrams and key data
graphics that will guide day-to-day practice. He writes as if you and he are
both completing patient rounds together. Brian is to be commended for
capturing the essence of treating this formidable clinical challenge and
demystifying the stages of heart failure. I learned from reading this book
and know you will, too.
—Sidney C. Smith, Jr., MD, FACC, FAHA, FESC, FACP
Professor of Medicine, University of North Carolina at Chapel Hill
Past President, American Heart Association
Past President, World Heart Federation


PREFACE
I have written this book to enable the reader to craft solutions for patients
to breathe comfortably, reclaim their previous lifestyles, and forestall premature death. Whereas many textbooks cull diverse expert opinions, my
intent is to provide a balanced perspective that concisely “separates the
wheat from the chaff.” For the trainee, a familiarity with these fundamentals can provide a basis for future practice; for the experienced practitioner,
this book may inspire patient care beyond a previous standard.
The pandemic of heart failure parallels an unprecedented extension
of the human lifespan over the last century. While heart failure can occur
at any age, those who live longer are more likely to succumb to the culmination of a lifetime of cardiovascular insults. Fortunately, advances have
occurred. Modifiable risks have been identified. Widely available diagnostic tools allow early intervention. Multiple pharmacologic agents have

achieved class I guideline treatment recommendations. Medical devices
have demonstrated surprising efficacy. Applications derived from molecular biology have entered the medical arena.
In 2001, the American College of Cardiology and the American
Heart Association defined 4 progressive stages of heart failure:
A: Risk factors for heart failure.
B: Asymptomatic ventricular dysfunction.
C: Clinical heart failure.
D: Advanced heart failure.

These 4 stages were most recently expanded and refined in 2013.
This book emphasizes the understanding of these stages as a continuum
and provides a scaffold to build tailored approaches to treatment and
improve individual outcomes.
—Dr. Brian E. Jaski

xv



ABBREVIATIONS
AA
ACCF
ACE
ACEI
ACLS
ADA
ADH
ADHF
AHA
AHFS

AKI
AL
ALT
ALVD
AMPK
ANP
ARB
AST
AT
ATP

amyloid A protein

ATTR

American College of
Cardiology Foundation

AV

angiotensin converting
enzyme
angiotensin converting
enzyme inhibitor
advanced cardiac life
support
American Diabetes
Association

∆AVO2

BiPAP
BMI
BNP

antidiuretic hormone
(vasopressin)

BSA

acute decompensated heart
failure

Ca

American Heart
Association
acute heart failure
syndrome
acute kidney injury
amyloid light-chain protein
alanine transaminase (also
called SGPT)

BUN
2+

CABG
CAD
cAMP

CBC
CCr
CDC

asymptomatic left ventricular dysfunction

cGMP

adenosine monophosphate-activated protein
kinase

CHF

atrial natriuretic peptide

CMR

angiotensin II receptor
blocker

CNP

aspartate aminotransferase
(also called SGOT)
anaerobic threshold
adenosine triphosphate

CKD

CPAP

CPS
CR
CRS

amyloidosis
transthyretin-related
atrioventricular
arteriovenous oxygen
difference* (difference
between arterial and venous
oxygen concentration)
biphasic positive airway
pressure
body mass index (kg/m2)
b-type natriuretic peptide
body surface area
blood urea nitrogen
calcium
coronary artery bypass
graft
coronary artery disease
cyclic adenosine
monophosphate
complete blood count
creatinine clearance rate
Centers for Disease
Control
cyclic guanosine
monophosphate
congestive heart failure

chronic kidney disease
cardiac magnetic resonance
c-type natriuretic peptide
continuous positive airway
pressure
cardiopulmonary support
creatinine
cardiorenal syndrome

*See Chapter 2 for formula and calculation.

xvii


xviii • Abbreviations

CRT
CSA
CT
CTCA
cTn
CVP
CysC
Cyt
CXR
DBP
DIAS
DNA
DPTI
DT

ECG
ECLS
ECMO
EF
eGFR
EMB
ESR
FM
GFR
GGT
GLA
GTP
HCM
HF

cardiac resynchronization
therapy
central sleep apnea
computed tomography
computed tomography
coronary angiography
cardiac troponin
central venous pressure
cystatin C

HF-pEF
HF-rEF
HFE
HLVH
HOCM

cytoplasm

HR

chest x-ray

HTN

diastolic blood pressure

IABP

diastolic

ICD

deoxyribonucleic acid
diastolic pressure–time
index
deceleration time
electrocardiography
extracorporeal life support
extracorporeal membrane
oxygenation
ejection fraction
estimated glomerular
filtration rate

IHSS

INR
IVD
IV
J-G
LA
LAMP2

endomyocardial biopsy

LV

erythrocyte sedimentation
rate

LVAD

fulminant myocarditis
glomerular filtration rate

LVDP

gamma-glutamyl
transferase

LVEF

α-Galactosidase A

LVH

guanosine triphosphate
hypertrophic
cardiomyopathy
heart failure

LVOT
LVSD

heart failure with
preserved ejection fraction
heart failure with reduced
ejection fraction
gene and protein that
regulate iron absorption
hypertensive left
ventricular hypertrophy
hypertrophic obstructive
cardiomyopathy
heart rate
hypertension
intra-aortic balloon pump
implantable cardioverterdefibrillator
idiopathic hypertrophic
subaortic stenosis
international normalized
ratio
intravenous diuretics
intravenous
juxtaglomerular
left atrial

lysosomal-associated
membrane protein 2
left ventricle / left
ventricular
left ventricular assist
device
left ventricular diastolic
pressure
left ventricular ejection
fraction
left ventricular
hypertrophy
left ventricular outflow
tract
left ventricular systolic
dysfunction


Abbreviations • xix

MCS
MDRD
MI
mPTP
MR
MRA
MRI
mRNA
NCEP
NE

NEP
NGAL
NIH

mechanical circulatory
support
modification of diet in
renal disease
myocardial infarction
mitochondrial permeability
transition pores
magnetic resonance

OSA
PCWP
PET
PND
PPVO2
PUF
RAAS
rAAV

RDA
RER
RNA
RV
S-ICD

mineralocorticoid receptor
antagonist

SBP

magnetic resonance
imaging

SCr

SCD

messenger ribonucleic acid

Scys

National Cholesterol
Education Program

SERCA2a

SDB

norepinephrine
neutral endopeptidase
neutrophil gelatinaseassociated lipocalin
National Institutes of
Health

NT-proBNP N-terminal pro-B-type
natriuretic peptide
NYHA

RCM

New York Heart
Association
obstructive sleep apnea
pulmonary capillary wedge
pressure
positron-emission
tomography
paroxysmal nocturnal
dyspnea
percent predicted peak
oxygen consumption
peripheral ultrafiltration
renin-angiotensinaldosterone system
recombinant adenoassociated virus

SGOT
SGPT
SIRS
SPECT
SR
STEMI
SYS
SV
TAVR
TDI
TEE
TIMI

TMEM43
TSH

restrictive cardiomyopathy
recommended dietary
allowance
respiratory exchange ratio
ribonucleic acid
right ventricular
subcutaneous implantable
cardioverter-defibrillator
systolic blood pressure
sudden cardiac death
serum creatinine
serum cystatin C
sleep-disordered breathing
sacro(endo)plasmic
reticulum calcium
transport ATPase 2a
serum glutamic oxaloacetic
transaminase
serum glutamic pyruvic
transaminase
systemic inflammatory
response syndrome
single-photon-emission
computed tomography
sarcoplasmic reticulum
ST-elevation myocardial
infarction

systolic
stroke volume
transcatheter aortic valve
replacement
tissue Doppler imaging
transesophageal
echocardiogram
thrombolysis in myocardial
infarction
transmembrane protein 43
thyroid stimulating
hormone


xx • Abbreviations

TTI
TTR
UO
VAD
VHD

tension-time index
transthyretin
urine output
ventricular assist device
valvular heart disease

VO2

VT

W-IHM
WHF
WRF

oxygen consumption
ventricular tachycardia
wireless implantable
hemodynamic monitoring
worsening heart failure
worsening renal function


Introduction
Definitions of Heart Failure
Heart failure is not a single diagnosis, but rather a syndrome of multiple
etiologies. Like fever or jaundice, heart failure mandates an investigation
into specific causes to permit effective therapies. Unlike these other maladies, heart failure may evolve insidiously and initially elude detection.
Comorbidities commonly complicate assessment.
Beyond causing symptoms of vascular congestion, heart failure also
threatens life through pump dysfunction and sudden death. In contrast
to myocardial infarction where atherothrombosis is an accepted mechanism,1 the pathophysiology of the heart failure syndrome is more diverse
in initiation and progression. The 2013 ACCF/AHA Heart Failure
Guidelines defined heart failure as “a complex clinical syndrome that
results from any structural or functional impairment of ventricular filling
or ejection of blood.”2

STAGE A

At high risk for HF but
without structural heart
disease or symptoms of HF

STAGE B

Structural heart diease
but without signs or
symptoms of HF

STAGE C

Structural heart disease with
prior or current symptoms

STAGE D
Advanced HF

FIGURE 1 The 4 stages of heart failure designated by the ACCF/AHA including those
describing the risks for and those associated with manifest clinical heart failure. A
patient maintains his most advanced stage status even if symptoms improve.
The 4 Stages of Heart Failure © 2015 Brian E. Jaski. Cardiotext Publishing, ISBN: 978-1-935395-30-0.

1


2 • Introduction

Clinical Definition of Heart Failure
In clinical practice, the following simplified definition can serve as an

orientation for the 4 Stages of Heart Failure.
HEART PUMP INSUFFICIENCY RESULTING IN SYMPTOMS
Heart Pump:

A complete description of the heart includes vascular, electrical, hormonal,
and structural components. For heart failure to be present, however, there
must be impairment of the heart to move blood in the circulation. A way to
e ne impaire heart pump function is the inability of the heart to supply
bloo flo to meet the nee s of the bo y either at rest or ith activity, or to
o so ith increase left or right ventricular lling pressures. f importance,
this may occur with either a reduced or preserved ventricular ejection fraction.

Insufficiency:

The word “failure” implies a cessation of function, as in patients with
“renal failure” who are either on or in imminent need of dialysis. In heart
failure, heart pump insuf ciency oes not, in general, re uire complete
replacement therapy. This semantic difference may be important to
emphasize to patients or families with a new diagnosis of “heart failure.”

Resulting In:

is factors or asymptomatic car iac ysfunction often prece e the rst
symptoms of heart failure. Advances in understanding neurohumoral
mechanisms that impel this progression over time have le to signi cant
therapies for heart failure with reduced ejection fraction.

Symptoms:

Stages A and B of the American College of Cardiology/American Heart

ssociation classi cation of heart failure are asymptomatic an consi ere
pre-heart failure.2 clinical e nition of heart failure, ho ever, is con ne
to Stages C and D, characterized by current or previous symptoms associated
ith heart pump insuf ciency. ommon symptoms are shortness of breath
associated with lung congestion and peripheral edema.


References • 3

References
1. Nabel EG, Braunwald E. A tale of coronary artery disease and myocardial infarction.
N Engl J Med. 2012;366(1):54-63.
2. Yancy CW, et al. 2013 ACCF/AHA guideline for the management of heart failure: a
report of the American College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-e239.