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PATHOPHYSIOLOGY OF

HEART FAILURE

Sara Paul DNP, FNP, FAHA, CHFN, FHFSA

HF Pathophysiology

1. Initiating Cause/Event

2. Neurohormonal Activation

3. Immune Activation

4. Physiologic Alterations (remodeling)

• Systolic vs. diastolic dysfunction

5. Hemodynamic Changes

• Right vs. left-sided HF

6. Symptom Development

Initiating Causes/Events

• Ischemic heart disease/CAD

• Hypertension

• Valvular disease

• Genetic abnormalities, hypertrophic cardiomyopathies

• Congenital heart abnormalities/defects

• Peripartum cardiomyoathy

• Amyloidosis/sarcoidosis

• Infections (e.g., viral myocarditis, Chagas’ disease)

• Metabolic disorders (hyperthyroidism, diabetes)

• Toxins (e.g., alcohol or cytotoxic drugs)

• Prolonged arrhythmias

• Idiopathic cardiomyopathy

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Neurohormones in Heart Failure

• Norepinephrine

• Renin

• Angiotensin II

• Aldosterone

• Vasopressin

• Endothelin

• ANP, BNP

• Cytokines

• Nitric oxide

CNS sympathetic outflow

Disease progression

Cardiac sympathetic

activity

1-receptors

2-receptors

1-receptors

Vasoconstriction

Sodium retention

Myocardial toxicity

Increased arrhythmias

Sympathetic

activity to kidneys

+ peripheral vasculature

Activation

of RAS1- 1-

Compensatory Mechanisms:

Sympathetic Activation in Heart Failure

RAAS Activation

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NE

UR

OH

OR

MO

NE

S

Natriuretic Neurohormones

• Natriuretic Peptides: Three known types

• Atrial Natriuretic Peptide (ANP)

• Predominantly found in the atria

• Diuretic and vasodilatory properties

• Brain Natriuretic Peptide (hBNP)

• Predominantly found in the cardiac ventricles

• Diuretic and vasodilatory properties

• C-type Natriuretic Peptide (CNP)

• Predominantly found in the central nervous system

• Limited natriuretic and vasodilatory properties

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Hemodynamic

(balanced vasodilation)

• veins

• arteries

• coronary arteries

Neurohormonal

aldosterone

norepinephrine

Renal

diuresis & natriuresis

Pharmacological Actions of hBNP

Abraham WT and Schrier RW, 1994 INHIBITED BY NEPRILYSN

BN

P C

on

cen

trat

ion

(pg

/mL

)

186 ± 22

791 ± 165

2013 ± 266

HF Severity

Mild

n = 27

Moderate

n = 34

Severe

n = 36

0

500

1000

1500

2000

2500

BNP Concentration

and Degree of HF Severity

Dao Q et al. J Am Coll Cardiol. 2001;37:379.

Antidiuretic Hormone (ADH) –

Vasopressin

• Activation of carotid sinus & aortic arch

baroreceptors due to low C.O. leads to ADH

release &

• stimulation of thirst

• promotes water retention

• leads to decreased plasma sodium concentration

(hyponatremia)

• increases SVR (hence, BP & afterload)

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Decreased systemic blood pressure

Central baroreceptors

Stimulation of hypothalamus, which produces

vasopressin for release by pituitary gland

Release of vasopressin by pituitary glandVasoconstriction

Increased systemic blood pressure

Vasopressin

*Note: water retention with extreme activation of this system

Endothelium-Derived

Vasoactive Substances

- Produced by a thin lining of cells within the arteries and veins called the endothelium

Endothelium-derived relaxing factors (EDRF) –Vasodilators:

• Nitric Oxide (NO) – diminished in African Americans

• Bradykinin (increased with ACE inhibitors)

• Prostacyclin – increases renal perfusion; blocked by NSAIDs

Endothelium-derived constricting factors (EDCF) – Vasoconstrictors:

• Endothelin I

Alterations in endothelium-dependent vasodilation --

Role of nitric oxideArtery Vein

Endothelial

Cells

Smooth muscle

Cells

Connective

tissue

Epithelial

Cells

Valve

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The story of nitric oxide and endothelin . . . .

• Increased endothelin OR decreased nitric oxide OR both

contribute to poor exercise tolerance in HF patients by

diminishing pulmonary and peripheral vasodilation

Immune Activation

Immune Activation in HF

• What are cytokines?

• Low molecular weight protein molecules released by most

cell types in response to a variety of stimuli, such as

cardiac injury

• Myocardial cells are capable of synthesizing pro-

inflammatory cytokines

• Can be produced in the absence of immune system

activation

• Negative inotropes, cause muscle breakdown/wasting

• Elevated levels associated with cardiac cachexia & worse

clinical outcomes

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Cytokines

• TNF-α

• Inflammatory cytokine found in myocardium,

skeletal muscle & circulation

• Promotes LV remodeling, negative inotrope

• Promotes skeletal muscle wasting &

apoptosis

• Found in high levels in cachectic patients

Cytokines

• Interleukins

• Interleukin-1 has neg inotropic effects

• Interleukin-6 - Patients with higher IL-6

levels have worse NYHA class & poor LV

function

“Cytokine Hypothesis” for HF

• At high concentrations in lab animals, HF phenotype develops--

• LV enlargement

• LV remodeling

• LV dysfunction

• Pulmonary edema

• Cytokines don’t cause HF, but contribute to progression of HF.

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TNF Overexpression in the heart: ABC = 24 week old transgenic mice (note LV dilatation)

DEF = age matched control mouse

Deleterious Effects of Inflammatory

Mediators in HF

• LV dysfunction

• LV enlargement & remodeling

• Pulmonary edema

• Cardiomyopathy

• Endothelial dysfunction

• Anorexia and cachexia

• Skeletal muscle wasting

• Disruption of collagen weave

• Fibrosis

NYHA Class as related to Cytokine Level

10

0

2

4

6

8

Normal I II III IV

NYHA Functional Class

Seta Y, Shan K, Bozkurt B et al. J Cardiac Failure 1996; 2:243-49

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Renin-Angiotensin-Aldosterone

Endothelin

Norepinephrine

Vasopressin

Natriuretic Peptides

Nitric Oxide

Bradykinins

Vasoconstriction

Sodium/Fluid Retention

Chronic Cardiac Stress Tissue Remodeling/Fibrosis

Vasodilation

Natriuresis/Diuresis

Cardiac Stress

Remodeling

Opposition of Neurohormonal Forces

in Heart Failure

Endogenous vasoconstrictors overpower

endogenous vasodilators. This is especially true

during exercise!

Endothelin

Aldosterone

Angiotensin II

Vasopressin

Norepinephrine

NO

ANP

BNP

Harmful

Helpful

Neurohormone Wars

The Dark Side

Angiotensin IIAldosteroneNorepinephrineVasopressinEndothelinCytokines

BNP

ANP

NO

Bradykinin

The Force

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Physiologic Alterations

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Normal

collagen struts

between myocytes

Disruption of

collagen struts due

to ischemia

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Remodeling of collagen weave in hypertrophy

Matrix metalloproteinases

(MMPs) are enzymes that

degrade collagen

“Slippage” of myocytes

Cardiac Myocyte

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Ventricular Remodeling

• The change in ventricular size, shape and function that

occurs in response to an index event.

• Neurohormone and cytokine activation enhance the

remodeling process after the index event & promote

progression of HF by stimulating further changes in

the myocytes.

Progressive dilation and hypertrophy in

ventricular remodelingTime

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Remodeling:

Myocardial thinning and hypertrophy

Pulmonary Vasculature

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Updated WHO Clinical Classification of

Pulmonary HTN (Dana Point, 2008)• 5 Main groups

1. Pulmonary arterial hypertension (PAH)

2. Pulmonary hypertension owing to left heart disease

3. Pulmonary hypertension owing to lung diseases and/or

hypoxia

4. Chronic thromboembolic pulmonary hypertension (CTEPH)

5. Pulmonary hypertension with unclear multifactorial

mechanisms

Simonneau et al. Updated Clinical Classification of Pulmonary Hypertension. JACC 2009, 54(1); S43-S54.

2. Pulmonary hypertension due to

left heart disease• Pulmonary venous hypertension

• Systolic dysfunction

• Diastolic dysfunction

• Valvular disease

• The most common

cause of pulmonary

hypertension

Pulmonary

Artery

Pulmonary

Veins

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Now let’s bring the kidneys into the

picture…..

How are the kidneys affected in

heart failure???

Traditional Assumption:

Renal dysfunction is secondary to renal hypoperfusion

due to decreased cardiac output with heart failure

NEW HYPOTHESIS:

Renal dysfunction in patients with heart failure is more

strongly associated with venous congestion than with

reduced cardiac output

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Cardiorenal syndrome

Arterial blood flow

Venous blood flow

> 0.3 mg or 25% increase in creatinine

Hemodynamic Changes

Pathophysiology: Symptoms vs

Disease Progression

What produces progression?

Neurohormonal abnormalities

• Activation of renin-angiotensin system (RAS) andsympathetic nervous system (SNS)

• Cytokines, endothelin, vasopressin, others, etc.

What produces symptoms?

Hemodynamic abnormalities

— Changes in cardiac function and peripheral hemodynamics

Cohn JN. N Engl J Med. 1996;335:490–498.

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Cardiac Performance• Preload

• End diastolic ventricular stretch (pressure)

• Determined by venous return (ventricular filling)

• Afterload

• Arterial pressure the ventricle must pump against; aortic

pressure for LV, pulmonary pressure for RV

• Increased by norepi, angiotensin II, vasopressin

Frank-Starling Curve

2-7 mmHg

25/9 mmHg

10mmHg

25/9 (14)

90-140/5-12

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Pulmonary Hypertension or Left Heart Failure

Right Heart

Failure

Venous

CongestionWorsening

Renal Function

Right heart failure: mitral stenosis

Valve stenosis

affecting right heart muscle

Some terminology:

LV Ejection Fraction• The percentage of blood volume ejected from the left

ventricle with each heartbeat.

• Normal = 60%

• Is a measurement of the strength of contraction

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2 Types of heart failure

Filling Dysfunction (HFpEF)

• Heart failure symptoms with EF 40%

• Hypertrophic CMP, HTN, Ischemia, Age

• Impaired relaxation

Contractile Dysfunction (HFrEF)

• Depressed contractility EF 40%

• CAD, Valve disease, Ischemic and Idiopathic

CMP

• Impaired contractility

Definition of Heart FailureClassification Ejection

Fraction

Description

I. Heart Failure with

Reduced Ejection Fraction

(HFrEF)

≤40% Also referred to as systolic HF. Randomized clinical trials have

mainly enrolled patients with HFrEF and it is only in these patients

that efficacious therapies have been demonstrated to date.

II. Heart Failure with

Preserved Ejection

Fraction (HFpEF)

≥50% Also referred to as diastolic HF. Several different criteria have been

used to further define HFpEF. The diagnosis of HFpEF is

challenging because it is largely one of excluding other potential

noncardiac causes of symptoms suggestive of HF. To date,

efficacious therapies have not been identified.

a. HFpEF, Borderline 41% to 49% These patients fall into a borderline or intermediate group. Their

characteristics, treatment patterns, and outcomes appear similar to

those of patient with HFpEF.

b. HFpEF, Improved >40% It has been recognized that a subset of patients with HFpEF

previously had HFrEF. These patients with improvement or recovery

in EF may be clinically distinct from those with persistently

preserved or reduced EF. Further research is needed to better

characterize these patients.

HFrEF HFpEF

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Symptom Development

Symptoms are the “Tip of the Iceberg”

in Heart Failure

Dyspnea

FatigueEdema

Orthopnea

Neurohormonal

Activation

Volume

Overload

Pressure

Overload

LV Remodeling

Fibrosis

Cytokines

Vasoconstriction

Index Event

Left Ventricular Remodeling

Neurohormonal Activation

Reduced Myocardial Function

Volume Overload & Elevated LV Filling Pressure

SymptomsDyspnea

Fatigue

Edema

Orthopnea/PND

Cough

Water is pushed out into interstitial space

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Definition of Heart Failure:

Old and New

Old definition

State in which the heart is unable to pump enough blood to meet the metabolic demands of the body

New definition

Complex clinical syndrome that results from structural and functional changes in the heart that all occur in the milieu of neurohormonal activationand cytokine release

A clinical syndrome or condition rather than a disease; the end result of a variety of diseases.

Summary

• Initiating Cause/Event

• Neurohormonal Activation

• Immune Activation

• Physiologic Alterations (remodeling)

• Systolic vs. diastolic dysfunction

• Hemodynamic Changes

• Right vs. left-sided HF

• Symptom Development