PATHOPHYSIOLOGY OF HEART FAILURE

[Pages:22]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

Compensatory Mechanisms: Sympathetic Activation in Heart Failure

CNS sympathetic outflow

Cardiac sympathetic activity

1receptors

2-

1-

receptors receptors

Sympathetic activity to kidneys + peripheral vasculature

1- 1-

Activation of RAS

Myocardial toxicity Increased arrhythmias

Vasoconstriction Sodium retention

Disease progression

RAAS Activation

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NEUROHORMONES

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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

3

Pharmacological Actions of hBNP

Hemodynamic (balanced vasodilation) ? veins ? arteries ? coronary arteries

Neurohormonal

aldosterone norepinephrine Renal diuresis & natriuresis

Abraham WT and Schrier RW, 1994

INHIBITED BY NEPRILYSN

BNP Concentration (pg/mL)

BNP Concentration and Degree of HF Severity

2500

2000

1500 1000

791 ? 165

500 186 ? 22

0

Mild

Moderate

n = 27

n = 34

HF Severity

2013 ? 266

Severe n = 36

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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Vasopressin

Decreased systemic blood pressure

Central baroreceptors

Increased systemic blood pressure

Stimulation of hypothalamus, which produces vasopressin for release by pituitary gland

Vasoconstriction

Release of vasopressin by pituitary gland

*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 oxide

Artery

Vein

Endothelial Cells

Valve

Smooth muscle Cells

Connective tissue

Epithelial Cells

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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 proinflammatory 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- ? 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 8 6 4

2

0

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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