Pathophysiology of Heart Failure

Heart Disease

Braunwald

CV R4 李威廷醫師Supervisor: 劉秉彥醫師

• Myocardial failure: myocardial infarction, acute myocarditis

• Heart failure: myocardial failure, acute AR, constrictive pericarditis

• Circulatory failure:

heart failure, hypovolemic shock, septic shock

Adaptive mechanisms• Frank-starling mechanism: preload (short-term)

• Neuroendocrine system: norepinephrine (short-term)

• Myocardial remodeling: with or without chamber dilatation (chronic or long-term)

Frank-starling mechanism: LVEDP v.s. ventricular performance

Vascular redistribution• Increase vasoconstrictor activity sympathetic nervous system

renin-angiotensin system

endothelin system

keep adequate oxygen to vital organs (brain, heart)

• Endothelial dysfunction ischemic- and exercise- induced vasodilation attenuated

L-arginine, NO

Peripheral hypoperfusion

• Non-vital organs: Anaerobic metabolism, lactic acidosis

• Skin: cold, dry turger

• Muscle: weakness

• Kidney: sodium and nitrogen retention

• Gut: decreased GI motility, GI upset

• Liver: hepatic dysfunction

Chronic myocardial remodeling (1)

• Pressure overload: increase ventricular wall thickness (concentric hypertrophy) (isometric)

• Volume overload: mild increase ventricular wall thickness (eccentric hypertrophy) (counterbalance the increased radius) (isotonic)

Left ventricular wall thickness vs Chamber radius

Apoptosis and necrosis

Molecular mechanism of myocardial remodeling and failure (Myocyte Loss)

• Necrosis: deprived of oxygen or energy

loss of membrane integrity influx of ECF cellular swelling release of proteolytic enzymes cellular disruption (subendocardial area)

(acute myocarditis, DCM, myocardial infarction)

• Apoptosis: specific genetic program

molecular cascade of degradation of nuclear DNA

(angiotensin II, NO, inflammatory cytokines, mechanical strain)

Molecular mechanism of myocardial remodeling and failure (Excitation-Contraction coupling alternation)

• Ca: contraction and relaxation;

• Force-frequency relationship: contractile force decrease, rates of stimulation increase

• Sarcoplasmic reticulum Ca-ATPase & phospholamban: Ca reuptake system (SERCA2)

• Na-Ca exchanger: removal Ca in diastole

• Ca free channel, voltage-dependent Ca channel:• Calsequestrin: major Ca binding protein in SR

Molecular mechanism of myocardial remodeling and failure (Contractile apparatus alternation)

• Reduction of myosin ATPase activity: qualitative, quantitative

• Myosin isoform changes: fetal and neonatal form

• Altered regulatory proteins: troponin-T1 T2

Molecular mechanism of myocardial remodeling and failure (Matrix alternation)

• Regulation of interstitial collagen:

• Collagen strut depletion:

• Interstitial matrix accumulation:

ACEI

Vicious cycles in the overloaded heart

Pathophysiology of diastolic heart failure

• Altered ventricular relaxation

relaxation: inactivation of contraction

isovolemic relaxation and early ventricular filling

SERCA2 and calcium pump

ischemia, elevated afterload

• Altered ventricular filling

wall stiffness

diastolic asynergy: regional abnormal relaxation

diastolic asynchony: no relaxation

ischemia, pericardial disease

Diastolic dysfunction mechanism

Neurohormonal, autocrine, & paracrine adjustments (1)

• Response to inadequate arterial volumesystolic HF

• Adrenergic• Renin-angiotensin-aldosterone• Vasopressin and endothelin

• Atrial natriuretic peptide (ANP)

Neuroendocrine, autocrine, & paracrine adjustments (2)

• Autonomic nervous system

Increased sympathetic activity: blood norepinephrine,

abnormal baroreflex (?)

Decreased parasympathetic activity:

Cardiac norepinephrine depletion: not clear

Beta1-adrenergic receptor density decrease, G protein:

local NE concentration, beta1-antagonist

Gs (stimulation), Gi (inhibition): adenynyl cyclase

Neuroendocrine, autocrine, & paracrine adjustments (3)

• Renin-angiotensin system (RAS)

Juxtaglomerular beta1-receptor: renin

Renal vascular baroreceptor: renin

Adrenergic nervous system: NE

• Tissue RAS: 90—99%

Early activation than blood RAS

• Angiotensin receptor: AT1, AT2

Neuroendocrine, autocrine, & paracrine adjustments (4)

• Arginine vasopressin (AVP): V1 receptor, cathecholamine

• Natriuretic peptides: Atrial-NP, Brain-NP, C-NP

• Endothelin: pulmonary vasoconstrictor, Killip stage

• Inflammatory cytokine: TNF-a, IL-1b; Ca & myocardium

• Nitric oxide: inhibit inflammatory cytokines, apoptosis

• Oxidative stress: (animal study)

Clinical Aspects of heart failure: high-output heart failure; pulmonary edema

CV R4 李威廷醫師Supervisor: 劉秉彥醫師

Nov 6th, 2003

Backward heart failure hypothesis

• Right ventricular failure as a sequence of left ventricular failure

• Ventricle failed to discharge its contents• Increase LVEDP• Blood accumulation and pressure arises in atrium and

venous system• The atrium contracts more vigorously• Venous and capillary pressure arise• Fluid transudation from capillary bed to interstitial space

Forward heart failure hypothesis

• Reduced cardiac output, then diminished perfusion of vital organs

• Sodium and water retention• Increased extracellular fluid • Congestion of organs and tissues

• Massive myocardial infarction both forward and backward heart failure hypothesis

Low output versus high output heart failure

• Low output heart failure congenital, valvular, rheumatic, hypertensive,

coronary, and cardiomyopathic heart failure

• High output heart failure thyrotoxicosis, arteriovenous fistula, anemia,

beriberi disease, Paget’s disease of bone

Causes of heart failure• Underlying disease: structural, vessel, or valvular

• Fundamental causes: increased hemodynamic burden or reduction in oxygen delivery

• Precipitating causes: specific causes or incidents

(avoidance of a precipitating cause can prevent heart failure)

Precipitating causes of heart failure (1)

• Inapposite reduction of therapy: Na, water, diuretics

• Arrhythmia: tachycardia, bradycardia, abnormal conduction

• Myocardial ischemia or infarction• Systemic infection: esp. pulmonary

• Pulmonary embolism

• Physical, emotional, and environmental stress

• Cardiac infection and inflammation: myocarditis • Development of an unrelated illness: ARF

Precipitating causes of heart failure (2)

• Cardiac depressant of salt-retaining drug: beta- blocker, isoptin, diltiazm, doxorubicin, cyclophosphamide

• Cardiac toxins: alcohol, cocaine

• High-output status: valvular heart disease, anemia, pregnancy

• A second form of heart failure: HCVD + AMI

Symptoms of heart failure

• Respiratory distress

• Reduced exercise capacity

• Physical findings

• Laboratory findings

• CXR

Respiratory distress

• Exertional dyspnea: the degreeof activity necessary tp induce the symptom

• Orthopnea: dyspnea at recumbent position, relieving by elevation of the head with pillows (not-specific)

• Paroxysmal nocturnal dyspnea: interstitial pulmonary edema bronchospasm wheezing (cardiac asthma)

• Dyspnea at rest

• Acute pulmonary edema

Pulmonary & Cardiac Dyspnea

1. Cough v.s. sitting up relief

2. Smoking history

3. Bronchodilator agent v.s. diuretics

Reduced exercise capacity (1)

• Mechanism Pulmonary vascular congestion

Inadequate blood flow to exercise muscle

Deconditioning of skeletal and respiratory muscles

Attenuated peripheral blood vessel resistance

Abnormal skeletal metabolism

Patient anxiety

Reduced exercise capacity (2)

• Exercise testing

Maximal exercise capacity: treadmill test (total oxygen uptakes)

reflecting central hemodynamic response adequacy

Submaximal exercise capacity: 6-minute walk test

reflecting regulation of blood flow to the skeletal muscle

• Other organs symptoms Brain (confusion, insomnia), urinary tract (nocturia)

Reduced exercise capacity (3)

• Functional classification: (New York Heart Association)

I: no limitation

II: slight limitation

III: marked limitation

IV: inability for any work without discomfort

• Quality of life:

reduce symptoms, prolong survival, and improve quality of life

Physical findings• General appearance: orthopnea, malnutrition, cyanosis

• Increased adrenergic activity: pallor, cold, diaphoresis

• Pulmonary rales• Systemic venous hypertension: JVE, Kussmaul’s sign

• Hepatojugular reflux: right side heart

• Congestive hepatomegaly• Edema: extracelluar fluid gain >4L

• Pleural effusion: R’t ± L’t

• Ascites: long-term systemic venous hypertension

Cardiac findings

• Cardiomegaly: nonspecific

• Gallop sounds: S3, S4

Pulsus alternans ± electrical alternans

Abnormal response to the valsalva maneuver

Low grade fever

Cardiac cachexia

Cheyne-Stokes respiration

Laboratory findings

• Electrolyte dilutional hyponatremia

elevated arginine vasopressin

hypokalemia hyperkalemia

• Liver function tests GOT, GPT, LDH

hyperbilirubinemia

PT prolong

albumin level

Chest roentgenogram

• Cardiothoracic ratio, heart volume:• Pulmonary vein engorgement: 13—17 mmHg

• Redistribution, cephalization: 18— 23 mmHg

• Acute pulmonary edema: > 20—25 mmHg

Prognosis • 5-year mortality: 50%• Median survival: M 1.7 years (1948--1988)

F 3.2 years

• Progressive heart failure and sudden cardiac death

High-output heart failure

• Anemia (Hb <8 gm/dL):

pale, easy fatigability, DOE, palpitation

tachycardia, MR (or TR)

• Systemic arteriovenous fistulas: congenital or acquired

thrill, pulsation, distal warm, Branham’s sign

• Hyperthyroidism: tachycardia, Af with RVR, widened pulse pressure

loud S1, reversible dilated cardiomyopathy

Pulmonary edema causes• Cardiogenic• High altitude pulmonary edema (HAPE): > 2500m

• Neurogenic pulmonary edema: trauma, SAH

• Narcotic overdose pulmonary edema: heroin impurity

• Pulmonary embolism• Eclampsia: 70% post partum

• Post carioversion• Post anesthesia• Post cardiopulmonary bypass• Hantavirus pulmonary syndrome