HEART FAILURE CHAPTER 6

Clinical studies show that blocking the effects of the RAAS in HF is associated with improved cardiac function and prolonged survival. Thus, ______________ and _______________ are the cornerstone of HF treatment.

angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)

Agents with proven benefits in improving sx, slowing disease progression, and improving survival in chronic HF target neurohormonal blockade include:

angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), β-adrenergic blockers, and aldosterone antagonists.

Table 6- 1 Causes of Heart Failure Systolic Dysfunction

(Decreased Contractility) Reduction in muscle mass (e.g., myocardial infarction) • Dilated cardiomyopathies • Ventricular hypertrophy • Pressure overload (e.g., systemic or pulmonary hypertension, aortic or pulmonic valve stenosis) • Volume overload (e.g., valvular regurgitation, shunts, highoutput statesDiastolic Dysfunction (Restriction in Ventricular Filling) • Increased ventricular stiffness • Ventricular hypertrophy (e.g., hypertrophic cardiomyopathy, pressure and/ or volume overload) • Infiltrative myocardial diseases (e.g., amyloidosis, sarcoidosis, endomyocardial fibrosis) • Myocardial ischemia and infarction • Mitral or tricuspid valve stenosis • Pericardial disease (e.g., pericarditis, pericardial tamponade)

Table 6- 2 Beneficial and Detrimental Effects of the Compensatory Responses in Heart Failure

(Table 6- 2).

Elevated aortic and systemic pressures result in an increase in what 2 things?

afterload and reduced SV.

EPIDEMIOLOGY AND ETIOLOGY Epidemiology HF is a major public health concern affecting approximately 6 million people in the United States. An additional 670,000 new cases are diagnosed each year. HF manifests most commonly in adults older than 60 years. The growing prevalence of HF corresponds to

(a) better treatment of patients with acute MIs who will survive to develop HF later in life, and (b) the increasing proportion of older adults due to the aging baby boomer population. The relative incidence of HF is lower in women compared with men, but there is a greater prevalence in women overall due to their longer life expectancy.

Symptoms of left versus right sided heart failure.

-Symptoms of left-sided heart failure include dyspnea, orthopnea, and paroxysmal nocturnal dyspnea (PND), ---Symptoms of right-sided heart failure include fluid retention, GI bloating, and fatigue.

Total estimated direct and indirect costs for managing both chronic and acute HF in the United States for 2009 was approximately $ 37 billion. Medications account for approximately how much of that cost?

10% of that cost. HF is the most common hospital discharge diagnosis for Medicare patients and the most costly diagnosis in this population.

What is the Frank-Starling mechanism?

Amount of stretch imposed on the muscle determines the strength of contraction. Within limits, the strength of ventricular contraction resulting in increased SV varies proportionally to its precontraction length.

________________ also potentiates the release of aldosterone from the adrenal glands and norepinephrine from adrenergic nerve terminals. Additionally, it induces vascular hypertrophy and remodeling in both cardiac and renal cells.

Angiotensin II

Arterial vasoconstriction leads to impaired forward ejection of blood from the heart due to an increase in:

afterload. This results in a decrease in CO and continued stimulation of compensatory responses, creating a vicious cycle of neurohormonal activation.

Even after remodeling occurs, the heart can maintain CO for many years. However, heart function will continue to deteriorate until progression to clinical HF. The timeline for remodeling varies depending on the cardiac insult. For example, in the setting of an acute MI, remodeling starts within a few days. _________ _______________ , however, is what progressively worsens HF, and therefore it is a major target of drug therapy.

Chronic remodeling

Angiotensin II stimulates the synthesis and release of

aldosterone.

Etiology HF is the eventual outcome of numerous cardiac diseases or disorders (Table 6- 1). HF can be classified by the primary underlying etiology as ischemic or nonischemic, with 70% of HF related to ischemia. The most common causes of HF are:

CAD, hypertension, and dilated cardiomyopathy. CAD resulting in an acute MI and reduced ventricular function is a common presenting history. Nonischemic etiologies include hypertension, viral illness, thyroid disease, excessive alcohol use, illicit drug use, pregnancy-related heart disease, familial congenital disease, and valvular disorders such as mitral or tricuspid valve regurgitation or stenosis.

There is growing evidence of a link between renal disease and HF. Renal insufficiency is present in one-third of HF patients and is associated with a worse prognosis. In hospitalized HF patients, the presence of renal insufficiency is associated with longer lengths of stay, increased in-hospital morbidity and mortality, and detrimental neurohormonal alterations. Conversely, renal dysfunction is a common complication of HF or results from its treatment. Renal failure is also a common cause for HF decompensation.

Cardiorenal Model

Describe the 2 types of ventricular hypertrophy:

Concentric hypertrophy occurs in response to pressure overload such as in long-standing hypertension or pulmonary hypertension, eccentric hypertrophy occurs after an acute MI. Eccentric hypertrophy involves an increase in myocyte size in a segmental fashion, as opposed to the global hypertrophy occurring in concentric hypertrophy.

Most HF is associated with evidence of:

LV systolic dysfunction (evidenced by a reduced EF) with or without a component of diastolic dysfunction, which coexists in up to two-thirds of patients.

Because of the complex nature of this syndrome, it has become exceedingly more difficult to attribute a specific sign or symptom as caused by either right ventricular failure (RVF; systemic congestion) or LVF. Therefore, the numerous signs and symptoms associated with this disorder are collectively attributed to

HF rather than to dysfunction of a specific ventricle.

Norepinephrine is a classic marker for SNS activation. It plays an adaptive role in the failing heart by stimulating

HR and myocardial contractility to augment CO and by producing vasoconstriction to maintain organ perfusion.

High-output HF is characterized by an inordinate increase in the body's metabolic demands that outpaces

an increase in cardiac output (CO) of a generally normally functioning heart.

____________ is controlled by the autonomic nervous system, where sympathetic stimulation of β-adrenergic receptors results in an increase in HR and CO.

Need to look up....

The clinician must identify potential reversible causes of HF exacerbations including prescription and nonprescription drug therapies, dietary indiscretions, and medication nonadherence. What 2 causes deserves special attention because it is the most common cause of acute decompensation and can be prevented.

Nonadherence with dietary restrictions or chronic HF medications. As such, an accurate history regarding diet, food choices, and the patient's knowledge regarding sodium and fluid intake (including alcohol) is valuable in assessing dietary indiscretion. Nonadherence with medical recommendations such as laboratory and other appointment follow-up can also be indicative of nonadherence with diet or medications.

Endothelin ET-1, one of the most potent physiological vasoconstrictors, is an important contributor to HF pathophysiology. ET-1 binds to two G-protein coupled receptors, endothelin-A (ET-A) and endothelin-B (ET-B). ET-A receptors mediate vasoconstriction and are prevalent in vascular smooth muscle and cardiac cells. ET-B receptors are expressed on the endothelium and in vascular smooth muscle, and receptor stimulation mediates vasodilation. Levels of ET-1 correlate with HF functional class and mortality.

OMG my brain is melting.

Neurohormonal Model Development begins with an initial precipitating event or myocardial injury resulting in a decline in CO, followed by the compensatory mechanisms previously discussed. This includes activation of neurohormonal pathways with pathological consequences including the

RAAS, SNS, endothelin, and vasopressin, and those with counterregulatory properties such as the natriuretic peptides and nitric oxide. This model currently guides our therapy for chronic HF in terms of preventing disease progression and mortality.

Cardiac remodeling occurs as a compensatory adaptation to a change in wall stress and is largely regulated by neurohormonal activation, with ______________ and __________ being key stimuli.

angiotensin II and aldosterone

Proinflammatory Cytokines Inflammatory cytokines have been implicated in the pathophysiology of HF. Several proinflammatory (e.g., tumor necrosis factor [TNF]-α, interleukin-1, interleukin-6, and interferon-γ) and anti-inflammatory cytokines (e.g., interleukin-10) are overexpressed in the failing heart. The most is known about

TNF-α, a pleiotropic cytokine that acts as a negative inotrope, stimulates cardiac cell apoptosis, uncouples β-adrenergic receptors from adenylyl cyclase, and is related to cardiac cachexia. The exact role of cytokines and inflammation in HF pathophysiology continues to be studied.

Abnormal ventricular filling (diastolic dysfunction) and/ or ventricular contraction (systolic dysfunction) can result in

a similar decrease in CO and cause HF symptoms.

Isolated diastolic dysfunction, occurring in approximately 1/3 of HF patients, is diagnosed when:

a patient exhibits impaired ventricular filling with or without accompanying HF symptoms but normal systolic function.

HF can also be classified based on the main component of the cardiac cycle leading to impaired ventricular function. A normal cardiac cycle depends on two components:

systole and diastole. Expulsion of blood occurs during systole or contraction of the ventricles; diastole relates to filling of the ventricles.

SV is relatively fixed in HF; thus HR becomes the major determinant of CO. Although this mechanism increases CO acutely, the chronotropic and inotropic responses to sympathetic activation increase myocardial oxygen demand, worsen underlying ischemia, contribute to proarrhythmia, and further impair both:

systolic and diastolic function.

In the setting of a sustained loss of myocardium, a number of mechanisms aid the heart when faced with an increased hemodynamic burden and reduced CO. They include the following:

the Frank-Starling mechanism, tachycardia and increased afterload, and cardiac hypertrophy and remodeling.

Heart failure (HF) is defined as the inadequate ability of:

the heart to pump enough blood to meet the blood flow and metabolic demands of the body.

Cardiac remodeling entails changes in myocardial and extracellular matrix composition and function that results in both structural and functional alterations to

the heart.

The decrease in renal perfusion is sensed by the juxtaglomerular cells of the kidneys leading to the release of:

renin and initiation of the cascade for production of angiotensin II. This results in activation of the renin-angiotensin-aldosterone system (RAAS).

Ventricular dysfunction can also involve either the left or right chamber of the heart or both. Describe symptoms of right sided HF vs left sided HF:

right-sided failure manifests as systemic congestion, whereas left-sided failure results in pulmonary symptoms.

Counterregulatory Hormones (Natriuretic Peptides, Bradykinin, and Nitric Oxide) Atrial natriuretic peptide (ANP) and B-type (formerly brain) natriuretic peptide (BNP) are endogenous neurohormones that regulate

sodium and water balance.

Aldosterone potentially contributes to disease progression via sympathetic potentiation and ventricular remodeling. In addition, the combination of these multiple effects is likely responsible for the increased risk of:

sudden cardiac death attributed to aldosterone. As elevated aldosterone concentrations have been associated with a poorer prognosis in HF, its blockade has become an important therapeutic target for improvement of long-term prognosis.

Neurohormonal Model Development and progression of HF involves activation of neurohormonal pathways including the:

sympathetic nervous system and the RAAS.

Development and progression of heart failure involves activation of neurohormonal pathways, including the

sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS).

Tx of acute heart failure targets relief of congestion and optimization of cardiac output utilizing oral or IV diuretics, IV vasodilators, and when appropriate, inotropes. Current treatment strategies in acute heart failure target:

improving hemodynamics while preserving organ function.

Although hypertrophy helps to reduce cardiac wall stress in the short term, continued hypertrophy accelerates myocyte cell death through an overall

increase in myocardial oxygen demand.

Aldosterone in turn stimulates sodium and water retention in an attempt to

increase intravascular volume and hence preload.

Contractility, aka the ________ state of the heart, is an intrinsic property of cardiac muscle incorporating fiber shortening and tension development.

inotropic

Ejection fraction (EF) is the fraction of the volume present at the end of diastole that is pushed:

into the aorta during systole.

The resulting increase in afterload contributes to an increase in myocardial oxygen demand and opposes the desired increase in SV. In the kidneys, angiotensin II enhances renal function acutely by raising

intraglomerular pressure through constriction of the efferent arterioles.

Vasopressin type 1a stimulation leads to vasoconstriction, whereas actions on the V2 receptor cause free water retention through aquaporin channels in the collecting duct. Vasopressin increases:

preload, afterload, and myocardial oxygen demand in the failing heart.

The clinician must identify potential reversible causes of heart failure exacerbations, including:

prescription and nonprescription drug therapies, dietary indiscretions, and medication nonadherence.

General therapeutic management goals for chronic heart failure focus on:

preventing onset of clinical symptoms or reducing symptoms, preventing or reducing hospitalizations, slowing or preventing disease progression, improving quality of life, and prolonging patient survival.

However, excess levels of norepi are directly cardiotoxic. In addition, sympathetic activation increases the risk for

arrhythmias, ischemia, and myocyte cell death through increased myocardial workload and accelerated apoptosis (i.e., programmed cell death). Ventricular hypertrophy and remodeling are also influenced by norepinephrine.

Earlier models of HF focused on the hemodynamic consequences of volume overload from excess sodium and water retention, decreased CO secondary to impaired ventricular function, and vasoconstriction. Congestion was a result of fluid backup due to inadequate pump function. Therefore, drug therapy was focused on relieving excess volume using diuretics, improving pump function with inotropic agents, and alleviating vasoconstriction with vasodilators. Although these agents improved HF symptoms, they did little to slow the progressive decline in:

cardiac function or to improve survival.

Precipitating and Exacerbating Factors in Heart Failure HF patients exist in one of two clinical states. When a patient's volume status and symptoms are stable, their HF condition is said to be "compensated." In situations of volume overload or other worsening symptoms, the patient is considered "decompensated." Acute decompensation can be precipitated by numerous etiologies that can be grouped into 3 types causes:

cardiac, metabolic, or patient-related causes (Table 6- 3).

An increase in venous return to the left ventricle results in the stretch of

cardiomyocyte sarcomeres (or contractile units) and a subsequent increase in the number of cross-bridges formed between actin and myosin myofilaments.

Plasma norepinephrine concentrations are elevated proportionally to HF severity, with highest levels correlating to the poorest prognosis. Several mechanisms relate to diminished responsiveness to __________________ (e.g., norepinephrine) as cardiac function declines.

catecholamines

Diuretics are used for relief of acute CHF symptoms of:

congestion and maintenance of euvolemia.

In the kidneys, angiotensin II enhances renal function acutely by raising intraglomerular pressure through

constriction of the efferent arterioles.

The most common causes of heart failure are

coronary artery disease (CAD), hypertension, and dilated cardiomyopathy.

Sympathetic activation also enhances contractility by increasing:

cytosolic calcium concentrations.

In the setting of a sudden decrease in CO, the natural response of the body is to

decrease blood flow to the periphery to maintain perfusion to the vital organs such as the heart and brain. Therefore, renal perfusion is compromised due to both the decreased CO as well as the shunting of blood away from peripheral tissues.

What do Natriuretic peptides do?

decrease sodium reabsorption in the collecting duct of the kidney. cause vasodilation through the cyclic guanosine monophosphate (cGMP) pathway.

A failing left ventricle causes fluid to back up in the lungs, and a patient with right ventricular failure would exhibit systemic symptoms of congestion. Congestion is the most common symptom in HF, followed by symptoms related to decreased perfusion to peripheral tissues including

decreased renal output, mental confusion, and cold extremities.

Long-standing hypertension is the leading cause of:

diastolic dysfunction.

Nonpharmacologic treatment of CHF involves:

dietary modifications such as sodium and fluid restriction, smoking cessation, timely immunizations, and supervised regular physical activity.

Arginine Vasopressin Higher vasopressin concentrations are linked to ____________ ___________ and a poor prognosis in HF. Vasopressin exerts its effects through vasopressin type 1a (V1a) and vasopressin type 2 (V2) receptors.

dilutional hyponatremia

It is important to remember that congestion develops behind the failing ventricle, caused by the inability of that ventricle to eject the blood that it receives from the atria and venous return. As such, signs and symptoms may be classified as left sided or right sided. Symptoms of left-sided HF include:

dyspnea, orthopnea, and paroxysmal nocturnal dyspnea (PND),

Afterload is the resistance to ventricular ejection and regulated by what 3 things?

ejection impedance, wall tension, and regional wall geometry.

Activation of the compensatory mechanisms occurs in an effort to increase CO and preserve blood flow to vital organs. However, the increase in preload and afterload in the setting of a failing ventricle leads to:

elevated filling pressures and further impairment of cardiac function, which manifests as systemic and/ or pulmonary congestion.

Aldosterone's contribution to HF pathophysiology is also multifaceted. Renally, aldosterone causes sodium and water retention in an attempt to enhance intravascular volume and CO. This adaptive mechanism has deleterious consequences because excessive sodium and water retention worsen the already

elevated ventricular filling pressures.

In HF, the changes in cardiac size, shape, and composition are pathological and detrimental to heart function. In addition to myocyte size and extracellular matrix changes, heart geometry shifts from an

elliptical to a less efficient spherical shape.

Contractility is influenced to a large degree by adrenergic nerve activity and circulating catecholamines such as _______ and ________ .

epinephrine and norepinephrine.

Aldosterone also contributes to electrolyte abnormalities seen in HF patients. Hypokalemia and hypomagnesemia contribute to the increased risk of arrhythmias. In addition, evidence supports the role of aldosterone as an etiological factor for myocardial fibrosis and cardiac remodeling by causing increased

extracellular matrix collagen deposition and cardiac fibrosis.

Symptoms of right-sided HF include

fluid retention, GI bloating, and fatigue.

CLINICAL PRESENTATION AND DIAGNOSIS OF CHRONIC HEART FAILURE In low-output HF, symptoms are generally related to either congestion behind the failing ventricle( s), or _________ , or both.

hypoperfusion (decreased tissue blood supply), or both.

In a healthy heart, a large increase in CO is usually accomplished with just a small change in preload. However, in a failing heart, alterations in the contractile filaments reduce the ability of cardiomyocytes to adapt to increases in preload. Thus, an increase in preload:

impairs contractile function in the failing heart and results in a further decrease in CO.

Adrenergic receptor desensitization and down-regulation (decreased receptor number and postreceptor responses and signaling) occurs under sustained __________ ___________ .

sympathetic stimulation. The desensitization contributes to further release of norepinephrine. β-Adrenergic blocking agents, although intrinsically negatively inotropic, have become essential therapy for chronic HF.

Although most patients initially have ______ ventricular failure (pulmonary congestion), the ventricles share a septal wall, and because LVF increases the workload of the right ventricle, both ventricles eventually fail and contribute to the HF syndrome.

left

More commonly, HF is a result of

low CO secondary to impaired cardiac function. The term heart failure refers to low-output HF for the purposes of this chapter.

Angiotensin II is a key neurohormone in the pathophysiology of HF. The vasoconstrictive effects of angiotensin II lead to an increase in systemic vascular resistance (SVR) and blood pressure. The resulting increase in afterload contributes to an increase in

myocardial oxygen demand and opposes the desired increase in SV.

Another mechanism to maintain CO when contractility is low is to increase HR. This is achieved through sympathetic nervous system (SNS) activation and the agonist effect of

norepinephrine on β-adrenergic receptors in the heart.

The term acute heart failure (AHF) is used to signify either an acute decompensation of a patient with a history of chronic HF or to refer to a patient presenting with new-onset HF symptoms. Terms commonly associated with HF, such as cardiomyopathy and LV dysfunction, are not equivalent to HF but describe:

possible structural or functional reasons for the development of HF.

SV volume is determined by factors regulating

preload, afterload, and contractility.

Angiotensin II is a key neurohormone in the pathophysiology of HF. The vasoconstrictive effects of angiotensin II lead to an increase in:

systemic vascular resistance (SVR) and blood pressure.

PATHOPHYSIOLOGY A basic grasp of normal cardiac function sets the stage for understanding the pathophysiological processes leading to HF and selecting appropriate therapy for HF. CO is defined as:

the volume of blood ejected per unit of time (liters per minute) and is a major determinant of tissue perfusion. CO is the product of heart rate (HR) and stroke volume (SV):

SV is:

the volume of blood ejected with each systole.

Combination therapy with hydralazine and isosorbide dinitrate is an appropriate substitute for angiotensin II antagonism in those patients who:

unable to tolerate an ACE inhibitor or ARB or as add-on therapy in African Americans.

Activation of both the RAAS and the SNS also contribute to _________________ in an attempt to redistribute blood flow from peripheral organs such as the kidneys to coronary and cerebral circulation.

vasoconstriction

Nitric oxide's production is affected by the enzyme inducible nitric oxide synthetase (iNOS), which is upregulated in the setting of HF, likely due to increased levels of angiotensin II, norepinephrine, and multiple cytokines. In HF, the physiological response to nitric oxide appears to be blunted, which contributes to the imbalance between ___________ and ____________ .

vasoconstriction and vasodilation.

Bradykinin is part of the kallikrein-kinin system, which shares a link to the RAAS through ACE. Bradykinin is a vasodilatory peptide that is released in response to a variety of stimuli, including neurohormonal and inflammatory mediators known to be activated in HF. As a consequence, bradykinin levels are elevated in HF patients and thought to partially antagonize the

vasoconstrictive peptides.

Nitric oxide, a vasodilatory hormone released by the endothelium, is found in higher concentrations in HF patients and provides two main benefits in HF:

vasodilation and neurohormonal antagonism of endothelin.

However, the increase in glomerular filtration pressure may be offset by a reduction in renal perfusion secondary to angiotensin II's influence over the release of other vasoactive neurohormones such as

vasopressin and endothelin-1 (ET-1).

Preload is determined by what 2 things?

venous return as well as atrial contraction.

HF is a clinical syndrome characterized by a history of specific signs and symptoms related to congestion and hypoperfusion. Because HF can occur in the presence or absence of fluid overload, the term heart failure is preferred over the former term congestive heart failure. HF results from any structural or functional cardiac disorder that impairs the ability of the:

ventricle to fill with or eject blood. Many disorders, such as those of the pericardium, epicardium, endocardium, or great vessels, may lead to HF, but most patients develop symptoms due to impairment in left ventricular (LV) myocardial function.

Atrial natriuretic peptide is synthesized and stored in the atria, while BNP is produced mainly in the

ventricles. Release of ANP and BNP is stimulated by increased cardiac chamber wall stretch usually indicative of volume load.

Preload is a measure of

ventricular filling pressure, or the volume of blood in the left ventricle (aka as LV end-diastolic volume).

Ventricular hypertrophy, an adaptive increase in ventricular muscle mass due to the growth of existing myocytes, occurs in response to an increased hemodynamic burden such as:

volume or pressure overload.

Higher concentrations of natriuretic peptides correlate with a more severe HF functional class and prognosis. BNP is sensitive to _________ ___________

volume status; thus the plasma concentration can be used as a diagnostic marker in HF.