경희대학교 의과대학·의학전문대학원

(1)

4. Assessment of Cardiac Performance

D. End-systolic left ventricular pressure-volume relationship

useful index of vent. performance : independ. of both preload, afterload at any level of myocardial contractility

left ventricular end-systolic volume 은 end-systolic pressure 와 역비례

preload and afterload 변화 no change in contractility, ESPVR is unchanged

Contractility 증가 : ESPVR : left 로 이동

(lower ESV at any ESP) SV증가 (1→ 3).

(2)

(3)

Normal and Abnormal Myocardial Function

The Failing Heart

Introduction

Mechanisms of Heart Failure

Neurohumoral and Cytokine Adjustments

(4)

VENTRICULAR EJECTION and Filling ; ventricular function curve

Heart as a pump : (Frank-Starling relation).

relation between EDV (length of the muscle fibers) and stroke volume Stroke volume : diastolic fiber length (EDV = preload) 와 비례

arterial resistance (afterload = BP) 와 반비례 Level of contractility

Relation between ventricular end-diastolic pressure ( = EDV) and stroke work of ventricle (ventricular function curve)

(5)

D. THE FAILING HEART: heart failure (HF)

심장의 구조 , 기능적 장애로 metabolizing tissues 의 요구에 부합되게 심박출 을 하지 못하거나 , LVEDV(P) 가 증가해야 가능한 상태

1.Systolic HF :

impaired myocardial contractility weak systolic contraction → ↓SV, CO cardiac dilatation, ↑LVEDP

dilated cardiomyopathy, cardiogenic shock in MI

2.diastolic HF

impaired relaxation, filling of ventricle ↑LVEDP

stiff, thickened ventricle

3.Coexist

cardiac hypertrophy and dilatation, systolic and diastolic HF

(6)

DIASTOLIC FUNCTION

a)Pressure-volume relation loop

1.acute ischemia ventricular relaxation 장애 2.↓ventricular distensibility restrictive cardiomyopathies extrinsic compression constricted or tamponade

3.↑ ventricular mass / wall thickness

a. concentric left ventricular hypertrophy, aortic stenosis, hypertension

hypertrophic cardiomyopathy b.↑intrinsic myocardial stiffness infiltration (e.g., amyloidosis) endomyocardial fibrosis, ischemia

4. volume overload

acute valvular regurgitation

acute left ventricular failure : myocarditis

(7)

D 1. MECHANISMS OF HEART FAILURE

ADAPTIVE AND MALADAPTIVE MECHANISMS

1. Frank-Starling mechanism : enhancing contraction ↑ preload

↑sensitivity to Ca2

ventricular dilatation -- maladaptive in severe valvular regurgitation, Laplace's law : ↑ wall stress, shortening 감소 .

(8)

Response Short-term Effects

(mainly adaptive: Acute HF)

Long-term Effects

(mainly deleterious; Chronic HF)

Salt and water

retention Augments preload Pulmonary congestion, anasarca Vasoconstriction Maintains pressure for

perfusion

vital organs (brain, heart)

Exacerbates pump dysfunction, increases cardiac energy

expenditure Sympathetic

stimulation Increases heart rate and ejection Increases energy expenditure Cytokine activation Vasodilatation Skeletal muscle catabolism

deterioration of endothelial function impaired contraction

LV remodeling. Hypertrophy Unloads individual muscle

fibers Deterioration and death of cardiac cells cardiomyopathy of overload Increased collagen May reduce dilatation Impairs relaxation

Sympathetic

desensitization Spares energy

(9)

2. Compensatory hypertrophy 3. Ventricular remodeling

insufficient hypertrophy Dilates, ↑wall stress ventricular hypertrophy 로 ventricular filling 장애 심근허혈 more spherical mechanical overload Hypertension Cardiomyopathy myocardial infarction.

(10)

(11)

Factors That Lead to the Progressive

Remodeling of the Left Ventricle

Cell Growth Fibrosis Apoptosis Counter-regulatory Factors

Angiotensin II Angiotensin II TNF-α ANP

Catecholamines Endothelin Fas ligand Bradykinin

Endothelin Aldosterone Nitric oxide

TNF-α TGF-β BNP

Growth hormone IGF

Cardiotrophin-1 Mechanical stretch

(12)

4. ALTERATIONS IN ENERGY METABOLISM

Acute, chronic ischemia : ↓supply of oxygen subendocardium ATP generation 과 creatine phosphate 감소

myocardial energy reserves 감소

5. ALTERATIONS IN SARCOMERIC PROTEINS

Hemodynamic overload, neurohormonal/ cytokine stimulation 으로 fetal sarcomeric proteins 발현 : contractility 저하

troponin T, myosin light chain kinase 2 변화로 myosin ATPase activity 저하

6. ABNORMALITIES OF EXCITATION-CONTRACTION COUPLING

disturbed delivery of Ca2+ to the contractile protein

7. MYOCARDIAL CELL DEATH

Apoptosis of myocytes

hemodynamic overload, neurohormone/ cytokine stimulation severe ischemia 로 유발되 → 생존 심근에 부하 증가

(13)

D 2. NEUROHUMORAL AND CYTOKINE ADJUSTMENTS

Activation of

sympathoadrenal system (SAS)

renin-angiotensin-aldosterone (RAAS) Endothelin

cytokines

tumor necrosis factor (TNF) argininevasopressin (AVP).

renin 분비 증가

Juxtaglomerular 기구내 ß-1 수용체 자극돼

(14)

D-2-1. Adrenergic nervous system

Circulating NE 증가

심장내 NE content 감소

beta1-adrenergic receptor density (downregulation) 심근 adenylyl cyclase activity 등은 저하

보상작용

심박동수 , 심근수축력증가 , RAA 자극으로 전부하 증가→심박출랼증가 해로운영향

세포내 갈슘이온 증가 . 축적으로 세포괴사 oxidative stress 항진과 Apoptosis

혈관수축 , 심장내압 증가 , 심근비후등 유발해 심근허혈 유발 심근비후 , 섬유화자동능 항진으로 부정맥빈도 증가

심박동수증가로 심근에너지요구량 증가와 허혈유발

(15)

D-2-2. renin-angiotensin-aldosterone system.

a)circulating angiotensin II

tissue renin-angiotensin system

cardiotoxic effect activate phospholipase C,

protein kinase C.

stimulates cardiac hypertrophy, ventricular remodeling.

peripheral vasoconstrictor release of NE,aldosterone

(16)

Effects of angiotensin-II

Vessels Vasoconstriction, Stimulates endothelin-1 release

Heart Inotropic and chronotropic effects, Coronary vasoconstriction Adrenal gland Aldosterone and adrenaline release

Brain Vasopressin release, Stimulation of the thirst center Increased sympathetic activation

Kidney Vasoconstriction (efferent > afferent arteriole) ↑ Na reabsorption , ↑ K excretion ,↓ renin release Platelets Stimulates adhesion and aggregation

Endothelial cells Inactivation of NO, Expression of endothelial oxLDL receptor Sympathetic ↑ peripheral noradrenergic neurotransmission

Fibrinolysis ↑ expression of PAI-1 and 2

Inflammation Activation / migration of macrophages ↑ adhesion molecules and cytokines (IL-6) Trophic effects

Hypertrophy of cardiac myocytes

Stimulation of vascular smooth muscle migration, proliferation Stimulates proto-oncogenes)

↑production of growth factors (PDGF, bFGF, IGF-1, TGFb1) Atherosclerosis ↑ NADH/NADPH oxidase activity and superoxide anion

(17)

b) Aldosterone 혈압 상승 전해질 소실 (K, Mg) 심근 섬유화 교감신경계 활성 D-2-3. Endothelin(ET) : ET-1 혈관내피세포 분비돼 는 혈관수축 peptide 수용체 : A 형 - 평활근 : 혈관수축 , 세포증식 , 섬유화 B 형 - 내피세포 : 혈관확장 , ET-1 합성억제

심부전 : Catecholamines, Angiotensin II, hypoxia 등 → ET-1 증가 후부하 증가 , 세포증식 , 섬유화 , 염증반응등 유발 심부전 진행 D-2-4. Inflammatory cytokines 심근수축력 저하 혈관내피세포 기능저하 Apoptosis oxidative stress 증가

(18)

(19)

(20)

Heart Failure (HF ; 심부전 )

심장의 구조 , 기능적 장애로 metabolizing tissues 의 요구에 부합되게 심박출을 하지 못하거나 , LVEDV(P) 가 증가해야 가능한 상태

모든 심장질환이 원인

허혈성심질환 , 판막증 , 고혈압성 심질환 , 심근증 Congestive Failure vs. Congestive State

Congestive state ： Overfilling of circulation without myocardial failure rapid infusion, anemia, chronic renal failure.

1.UNDERLYING CAUSES 모든 심장질환이 원인

(21)

2. PRECIPITATING CAUSES

1. Infection : fever, tachycardia, hypoxemia, metabolic demand 증가 2. Arrhythmias.

(a) Tachyarrhythmias : reduce ventricular filling, ischemic l

(b) atrial 과 ventricular dissociation : loss of atrial booster pump (c) abnormal intraventricular conduction

(d) bradyarrhythmias : cardiac output 저하

3. Physical, Dietary, Fluid, Environmental, and Emotional Excesses 4. Myocardial Infarction

5. Pulmonary Embolism 6. Anemia

7. Thyrotoxicosis and Pregnancy 8. Aggravation of Hypertension

9. Rheumatic, Viral, and Other Forms of Myocarditis 10. Infective Endocarditis

(22)

3. FORMS OF HEART FAILURE 1. Acute vs. Chronic Heart Failure

Acute ： Acute myocardial infarction, acute valvular regurgitation

Chronic ： Rheumatic valvular disease, hypertension, cardiomyopathy acute failure : sudden ↓ cardiac output, systemic hypotension

without peripheral edema,

chronic failure : arterial pressure well maintained, edema.

2. Left vs. Right Heart Failure

Left HF ： Coronary arteriosclerosis, hypertension : pulmonary congestion and edema.

Right HF ： most common causes : left ventricular failure pulmonary stenosis, pulmonary hypertension.

Systemic venous congestion and peripheral edema.

(23)

3. Backward vs. Forward Heart Failure

Backward ： Daming of blood proximal to the failing ventricle venous congestion-- sundrome of heart failure.

Forward ： decrease in cardiac output and underfilling of artery.

4. Low vs. High output failure

Low ： Common causes of HF, hypertension, vulvular High ： Cardiac output is normal or elevated

Hyperthyroidism, anemia, beriberi, A-V fistula,.

5. Congestive Failure vs. Congestive State 6. Systolic vs. Diastolic Failure

· Systolic failure ： inable to expel sufficient blood, inadequate CO. · Diastolic failure ： relax & filling 장애 , decreased compliance,

(24)

4. CLINICAL MANIFESTATIONS : Symptom

Dyspnea ： Dyspnea on exertion, the first symptom

Orthopnea ： Dyspnea soon after lying flat, relieved by sitting up

Cough,sputum ： Venous congestion , edema of tracheobronchial walls

Paroxysmal nocturnal dyspnea ： urgent respiratory distress, relief by sitting up open window to breath fesh air. labored respiration, cardiac asthma

Acute pulmonary edema ： Acute episode of LVF(acute myocardial infarction) Respiratory alkalosis ( hyperventilation) → respiratory acidosis

Hemoptysis ：

Rusty sputum-heart failure cells (alveolar macrophages- hemosiderin). Frank bloody sputum : pulmonary infarction.

Cheyne-Stokes respiration ： Periodic breathing of apena and hyperventilation Discrepancy between arterial and alveolar gas tension

Fatigue and weakness ： Reduction of perfusion of skeletal muscle Cerebral symptoms : Neurathenia, headache insomnia, anxiety Urinary symptoms : Nocturia, oliguria

(25)

5. Physical signs

General appearance ： Pale, breathlessness Skin ： Cold and sweaty

Pulse ： Weak, narrow pulse pressure

Pulsus alternans ： Alternating strong and weak pulse * Electrical alternans

Heart ： Enlarged

P2 accentuation, Gallop (ventricular, atrial, summation)

Lung ： Bilateral basal moist rale-terminal bronhioles and alveolar edema Systemic venous congestion : hallmark of right heart failure

Cardiac edema

prominent jugular vein

jugular pulse (prominent V wave-functional tricuspid insufficency) Hepatojugular refiux

Hepatomegaly-cardiac cirrhosis Extracellular fluid accumulation

Subcutaneous edema, hydrothorax, asctes, pericardial effusion, anasarca

(26)

6. 심부전의 진단

FRAMINGHAM CRITERIA FOR DIAGNOSIS OF C.H.F.

Major criteria

·Paroxysmal nocturnal dyspnea ·Neck vein distension

·Rales

·Cardiomegaly

·Acute pulmonary edema ·S3 gallop

·Increased venous pressure (> 16cmH2O) Minor criteria ·Extremity edema ·Night cough ·Dyspnea on exertion ·Hepatomegaly ·Pleural effusion

·Vital capacity reduced by one-third from normal ·Tachycardia (≥120 bpm)

Major or minor

·Weight loss ≥ 4.5 kg over 5 days treatment

(27)

(28)

Radiologic aspect

Enlarged cardiac silhoutte

Vasculature is prominent at apeces (pulmonary venous hypertension) redistribution of blood flow : edema & fibrosis of base

Prominent septal line - Kerley’s B line

(29)

DIASTOLIC FUNCTION

a)Pressure-volume relation loop

Normal

(30)

Normal : E>A

rapid in early diastole (E) than atrial systole(A)

impaired relaxation : E<A Pseudo-normalized E>A, ↓Em = Am Resrrictive ↑↑E>A, ↓Em = Am E/Em>12, Em = Am(5cm/sec) Doppler echo : flow velocity of mitral valve

tissue velocity of mitral annulus

MV 통과하는 헐류의 속도 (E : 70-80cm/s) 승모판륜의 속도 (Em : 10cm/s)

(31)

diastolic dysfunction progresses restriction to filling

(32)

Echocardiography

Left ventricular ejection fraction (LVEF) : systolic dysfunction Assessment of LV diastolic function

(33)

Stage A

high risk for developing HF

no structural disorder of the heart;

Stage B

structural disorder of the heart never developed symptoms of HF;

Stage C

past or current symptoms of HF underlying structural heart disease;

Stage D

end-stage disease

hypertension; CAD; DM cardiotoxic drug therapy

alcohol abuse; history of RF family history of cardiomyopathy LVH or fibrosis;

LV dilatation or hypocontractility; asymptomatic VHD; previous MI

LV syst dysfunction( Dyspnea / fatigue) asymptomatic, undergoing Tx for HF. maximal medical therapy and

require specialized interventions.

(34)

FUNCTIONAL CAPACITY OF HEART FAILURE (NYHA)

Class I ： without limiting of Ordinary physical activity Class II ： Slight limitation of physical activity.

Comfortable at rest, ordinary physical activity results Sxs Class III ： Marked limitation of physical activity.

Comfortable at rest, less than ordinary activity cause Sxs

Class IV ： Inability to carry out any physical activity without discomfort. Symptoms of cardiac insufficency persistent even at rest.

If any physical activity is undertaken, discomfort is increased

COMPLEMENT, DO NOT REPLACE NYHA CLASSES

NYHA Classes - shift back/forth

(in response to Rx and/or progression of disease Stages - progress in one direction due to cardiac remodeling

(35)

Management outline of CHF

Establish heart failure

Ascertain presenting features: pulmonary edema, exertional breathlessness, fatigue, peripheral edema

Assess severity of symptoms

Determine etiology of heart failure

Identify precipitating and exacerbating factors

Identify concomitant diseases relevant to heart failure and its management

Estimate prognosis

Assess complicating factors (e.g. renal dysfunction, arthritis) Choose appropriate management

Monitor progress and manage accordingly Counsel patient and relatives

8. MANAGEMENT OF CONGESTIVE HEART FAILURE

심부전 치료의 원칙과 목표

원인질환의 교정 , 진행을 억제 악화요소 제거 , 완화

(36)

Treatment options

Non-pharmacological management General advice and measures

Exercise and exercise training Pharmacological therapy

ACE-inhibitors Diuretics

Beta-adrenoceptor antagonists Aldosterone receptor antagonists Angiotensin receptor antagonists Cardiac glycosides

Vasodilator agents (nitrates/hydralazine) Positive inotropic agents

Anti-coagulation

Anti-arrhythmic agents Oxygen

Devices and surgery

Revascularization (catheter interventions and/or surgery), Other forms of surgery (mitral valve repair)

Bi-ventricular (multi-site) pacing

Implantable cardioverter defibrillator (ICD)

Heart transplantation, ventricular assist devices, and artificial heart

(37)

(38)

Stage A

high risk for HF

No structural D& Sx of HF

Stage A

high risk for HF

No structural D& Sx of HF Stage B Structural disease symptoms of HF Stage B Structural disease symptoms of HF Stage C Structural disease prior or current Sxs Stage C Structural disease prior or current Sxs Stage D Refractory HF Specia interventions Stage D Refractory HF Specia interventions hypertension CAD, DM

previous MI

LV systolic dysfx Asymp VHD known stru HD Dyspnea fatigue, Reduced Ex tolerance marked Sxs at rest despite max medical

therapy

Treat risk factors

Avoid toxics Avoid toxics ACE-i or ARB ACE-i or ARB ACE-i(ARB) ACE-i(ARB) ß ß--blockersblockers ACE-i(ARB) ACE-i(ARB) ß ß--blockersblockers Diuretics / Digitalis Diuretics / Digitalis Palliative therapy Palliative therapy

Mech. Assist device

Heart Transplant

Heart Transplant B. Treatment stratage according to NYHA Class

(39)

(40)

(41)

(42)

(43)

Stage A : High Risk for Developing Heart

Failure

Recommended Therapies to Reduce Risk Include:

Treating known risk factors (hypertension, diabetes, etc.)

with therapy consistent with contemporary guidelines Avoiding behaviors increasing risk (i.e., smoking

excessive consumption of alcohol, illicit drug use) Periodic evaluation for signs and symptoms of HF

Ventricular rate control or sinus rhythm restoration Noninvasive evaluation of LV function

Drug therapy –

Angiotensin Converting Enzyme Inhibitors (ACEI) Angiotensin Receptor Blockers (ARBs)

(44)

Stage B : Patients with Asymptomatic LV

Dysfunction

Recommended Therapies:

General Measures as advised for Stage A Drug therapy for all patients

ACEI or ARBs Beta-Blockers

ICDs in appropriate patients

Coronary revascularization in appropriate patients Valve replacement or repair in appropriate patients

Therapies NOT Recommended

Digoxin should not be used in patients with low EF, sinus rhythm, and no history of HF symptoms,

Calcium channel blockers with negative inotropic effects may be harmful i n asymptomatic patients with low LVEF and no symptoms of HF after MI.

(45)

Stage C : Patients with Past or Current Symptoms of Heart Failure

(Reduced LVEF with Symptoms) Generally Recommended Therapies:

General measures as advised for Stages A and B Drug therapy for all patients

Diuretics for fluid retention ACEI

Beta-blockers(BB)

Drug therapy for selected patients Aldosterone Antagonists :, ARBs

Digitalis : decrease hospitalizations for HF. Hydralazine/nitrates :

persistent Sxs after ACEI and BB

(46)

Stage C Therapy

Aldosterone Antagonists

moderate to severe symptoms of HF and reduced LVEF Creatinine ≤ to 2.5 mg/dL in men

Creatinine ≤ to 2.0 mg/dL in women Potassium<less than 5.0 mEq/L.

사망률 , 입원율 감소

Aldosterone escape 시기에

Routine combined use of ACEI, ARB, and aldo. antagonist : not recommend

Beta-blockers

proven to reduce mortality bisoprolol

carvedilol

(47)

Implantable Cardioverter-Defibrillators (ICDs) history of cardiac arrest

ventricular fibrillation

hemodynamically destabilizing ventricular tachycardia. post-MI with LVEF <30%,

Cardiac Resynchronization

QRS duration greater than 120 ms, LVEF less than or equal to 35% LVEDd> 55mm

Sinus rhythm, LBBB

Stage C :

Not Recommended

(48)

(49)

(50)

Stage C Therapy ; Normal LVEF with Symptoms = Diastolic HF

Recommended Therapies for Routine Use:

Treating known risk factor (hypertension) with therapy consistent with contemporary guidelines

Ventricular rate control for all patients Drugs for all patients

Diuretics

Drugs for appropriate patients – ACEI

ARBs

Beta-Blockers Digitalis

Coronary revascularization in selected patients

(51)

Differential Diagnosis in Patient with HF and

Normal LVEF with Symptoms

• Incorrect diagnosis of HF

• Inaccurate measurement of L

VEF

• Primary valvular disease

• Restrictive (infiltrative) cardio

myopathies

• Amyloidosis, sarcoidosis, hem

ochromatosis

• Pericardial constriction

• Episodic or reversible LV systo

lic dysfunction

• Severe hypertension, myocar

dial ischemia

• HF associated with high m

etabolic demand (high-ou tput states)

• Anemia, thyrotoxicosis, ar

teriovenous fistulae

• Chronic pulmonary diseas

e with right HF

• Pulmonary hypertension a

ssociated with pulmonary vascular disorders

• Atrial myxoma

• Diastolic dysfunction of u

ncertain origin

(52)

REDUCE THE CONGESTIVE STATE

Salt restriction, diuretics, ACE inhibitors Dialysis or plasmapheresis

MAINTAIN ATRIAL CONTRACTION Direct-current or pharmacological

cardioversion Sequential atrioventricular pacing

PREVENT TACHYCARDIA AND PROMOTE BRADYCARDIA

Beta blockers Radiofrequency ablation and pacing

TREAT AND PREVENT MYOCARDIAL ISCHEMIA

Nitrates, beta blockers, calcium blockers Bypass surgery, angioplasty

CONTROL HYPERTENSION

AND PROMOTE REGRESSION OF HYPERTROPHY

Antihypertensive agents

ATTENUATE NEUROHORMONAL ACTIVATION

Beta blockers, ACE inhibitors

PREVENT FIBROSIS AND PROMOTE REGRESSION OF FIBROSIS

ACE inhibitors, spironolactone Antiischemic agents

IMPROVE VENTRICULAR RELAXATION

Phosphodiesterase inhibitors Systolic unloading

(53)

Stage D : Refractory End-Stage HF

Recommended Therapies Include: Control of fluid retention

Referral to a HF program for appropriate pts Discussion of options for end-of-life care

Informing : option to inactivate defibrillator Device use in appropriate patients

Surgical therapy –

Cardiac transplantation

Mitral valve repair or replacement Drug Therapy –

Positive inotrope infusion as palliation

(54)

약제의 특성

1.ß-Adrenergic Blockers 1. Mechanism of action ↑ Density of ß1 receptors

Inhibit cardiotoxicity of catecholamines Neurohormonal activation

↓HR

Antiischemic, Antihypertensive

Antiarrhythmic, Antioxidant, Antiproliferative 2. Clinical Effects

Improve symptoms (only long term), survival

Reduce remodelling / progression

Reduce hospitalization / sudden death

3. Adverse Effects

HypotensionHypotension

Fluid retention / worsening HFFluid retention / worsening HF

FatigueFatigue

(55)

Start if Patient stable

No evidence of fluid retention

No need for i.v. inotropic drugs

Start ACE-I / diuretic first

Contraindications

Asthma (reactive airway disease)

AV block (unless pacemaker)

Symptomatic hypotension / Bradycardia

Diabetes is NOT a contraindication

4. Indications

Symptomatic heart failure

Asymptomatic Ventr. dysfunction - LVEF < 35 - 40 %

(56)

2. ACE-I.

Clinical Effects

Improve symptoms

Reduce remodelling / progression Reduce hospitalization

Improve survival

Indications

Symptomatic heart failure

Asymptomatic ventricular dysfunction LVEF < 35 - 40 %

Selected high risk subgroups

3. Diuretics

to control symptoms of fluid retention

Prevent progression from HT to HF

Spironolactone improves survival

Indications

Symptomatic HF, with fluid retention

Edema Edema Dyspnea Dyspnea Lung Rales Lung Rales Jugular distension Jugular distension Hepatomegaly Hepatomegaly

Pulmonary edema (Xray)

(57)

Clinical Effects Improve symptoms

Modest reduction in hospitalization Does not improve survival

4. Digitalis : Mechanism of Action.

Blocks Na+ / K+ ATPase

Blocks Na+ / K+ ATPase => ↑Ca+ +=> ↑Ca+ +

Inotropic effect

Natriuresis :

Natriuresis : inhibiting Na+-K+ ATPase in the kidney, Neurohormonal control

Neurohormonal control

↓

↓Plasma NoradrenalinePlasma Noradrenaline ↓

↓ Peripheral nervous system activityPeripheral nervous system activity ↓

↓ RAAS activity RAAS activity ↑

↑ Vagal toneVagal tone

Normalizes arterial baroreceptorsNormalizes arterial baroreceptors

Negative chronotropic effect

Slowed A-V junction by direct effect and reflex vagal action ↑ refractory period in A-V junction

(58)

Digitalis. Indications

Digitalis. Indications persistent symptoms of HF

severe SXs not responded to ACE-i + diuretics + beta-blockersACE-i + diuretics + beta-blockers

AF: to slow AV conduction(

AF: to slow AV conduction(adjunctive to beta-blockers)beta-blockers)

not indicated as primary therapy for the stabilization

in acute exacerbation of HF (fluid retention or hypotension)

Dose : 0.125 to 0.250 mg / day

Contraindications

Contraindications Digoxin toxicity

Advanced A-V block without pacemaker Bradycardia or sick sinus without PM PVC’s and VT

Marked hypokalemia

W-P-W with atrial fibrillation

little or no value

HF sinus rhythm

hypertrophic cardiomyopathy myocarditis, mitral stenosis

(59)

range of 0.5 to 1.0 ng per mL >2 ng per mL) : ↑ diditalis toxicity

Hypokalemia or hyperkalemia Hypomagnesemia, Hypercalcemia Hyponatremia Hypothyroid Renal function Acid-base imbalance

Concomitant drug administration Anesthetics

Catecholamines and sympathomimetic Antiarrhythmic agent ：

quinidine, amiodarone, verapamil erythromycin

itraconazole, cyclosporine,

Treatment of digitalis toxicity

Stop digitalis and diuretic Block ： Atropine, pacemaker

(60)

Drug Mechanism

Amiodarone ? ↓Renal clearance Verapamil ↓Renal clearance Nifedipine ↓Renal clearance Diltiazem ↓Renal clearance

Quinidine Displacement of protein binding, ↓renal Clearance Propafenone ↓Renal clearance

Captopril ? Renal clearance Carvedilol ↑Oral bioavailability Spironolactone ↓Renal clearance Amiloride ↓Renal clearance Triamterene ↓Renal clearance Macrolide Antibiotics

(erythromycin ) Altered gut flora, ↓renal Clearance Tetracycline Altered gut flora

Indomethacin ↓Renal clearance Alprazolam ? ↓Renal clearance Itraconazole ↓Renal clearance

Salbutamol Rifampin Sucralfate Cholestyramine Unknown Induction of gut P-glycoprotein ↓ gut absorption ↓ gut absorption ↑Serum digoxin Level ↓Serum digoxin Level

(61)

5. Spironolactone. Indications5. Spironolactone. Indications

Recent or current Sxs despite ACE-i, diuretics, dig. and b-blockers

Recommended in advanced heart failure (III-IV)

in addition to ACE-i and diuretics

Hypokalemia

Practical use Practical use

Do not use if hyperkalemia, renal insuf.

Monitor serum K+ at “frequent intervals”

Start ACE-i first

Start with 25 mg / 24h

If K+ >5.5 mmol/L, reduce to 25 mg / 48h

If K+ is low or stable consider 50 mg / day

(62)

VASODILATOR THERAPY : Principles of action ↓afterload : improve ventricular empting ： ↓ Reduce preload ：↓ venous tone

↓ ventricular dimension and myocardial oxygen requirement Effects of vasodilators

Agent Preload Afterload Nitroprusside +++ +++ Nitrate +++ ± Hydralazine ± +++ Captopril ++ ++

(63)

Nitrates. Clinical Use

CHF with myocardial ischemia

Orthopnea and paroxysmal nocturnal dyspnea In acute CHF and pulmonary edema : NTG sl / iv

Nitrates + Hydralazine : intolerance to ACE-I (hypotension, renal insufficiency)

Clinical indication of vasodilator therapy

1. Acute pulmonary edema 2. Acute myocardial infarction heart failure,

cardiogenic shock

mechanical complication ： Acute mitral regurgitation ventricular septal rupture

3. Acute left ventricular failure due to cardiac overload ： hypertensive crisis

acute aortic regurgitation 4. Chronic vasodilator therapy ：

(64)

7. Positive Inotropes 7. Positive Inotropes 1.Digitalis 1.Digitalis 2.Sympathomimetics 2.Sympathomimetics Catecholamines Catecholamines B-adrenergic agonists B-adrenergic agonists 3.Phosphodiesterase inhibitors 3.Phosphodiesterase inhibitors

Amrinone, Milrinone, Enoximone

4.Calcium sensitizers

Levosimendan, Pimobendan

May increase mortality

Exception: Digoxin, Levosimendan Use only in refractory CHF

(65)

Drugs to Avoid (may increase symptoms, mortality

Inotropes, long term / intermittentInotropes, long term / intermittent

Antiarrhythmics (except amiodarone)Antiarrhythmics (except amiodarone)

Calcium antagonists (except amlodipine)Calcium antagonists (except amlodipine)

Non-steroidal antiinflammatory drugs (NSAIDS)Non-steroidal antiinflammatory drugs (NSAIDS)

Tricyclic antidepressantsTricyclic antidepressants

Other Drugs. (only in selected patients)

Inotropics: refractory HFInotropics: refractory HF

Nitrates: ischemia, angina, pulmonary congestionNitrates: ischemia, angina, pulmonary congestion

ARB: Contraindications to ACE-iARB: Contraindications to ACE-i

Antiarrhythmics: (only amiodarone) H risk arrhyth.Antiarrhythmics: (only amiodarone) H risk arrhyth.

Anticoagulants: High risk of embolysmAnticoagulants: High risk of embolysm

(66)

(67)

(68)

Cardiogenic shock

Reduced blood pressure systolic BP<90 mmHg

drop of mean arterial pressure> 30 mmHg)

low urine output (<0.5 ml/kg/h) pulse rate >60

organ congestion.

(69)

Normal Pulmonary edema Cardiogenic shock Hypovolemic Tamponade 우심실경색증 폐색전증

systolic pump failure, acute mechanical defect (MR, AR, VSD)

Critical MS, AS

volume overload

(acute renal failure) noncardiogenic shock

(70)

Normal Hypovolemic shock Pulmonary edema Cardiogenic shock Fluid Normal BP : Vasodilators Low BP : Inotropics Vasopressors Diuretics Vasidilators NTGS, Nitroprusside

(71)

(72)

positive inotropic agents

Dopamine : precursor of norepinephrine hypotensive states and HF.

At very low doses : dilates renal and mesenteric

2 to 10 g/kg / min : myocardial ß-1 receptors µ 자극 . little tachycardia higher doses : α -adrenergic receptors,↑ arterial pressure.

Dobutamine : synthetic sympathomimetic agent

ß-1, 2, and α -1 receptors.

potent inotropic action, modest cardio accelerating ↓peripheral vascular resistance

(73)

Levosimendan

Ca sensitization (contractile proteins) : positive inotropic action Smooth m. K channel opening : peripheral vasodilation ph osphodioesterase inhibition

(74)

(75)

favorable long-term prognosis : valvular heart disease free of congestion,

low Survival ( 50% at 6 months) : refractory symptoms Poor prognosis

depressed ejection fraction (<15%),

reduced maximal O2 uptake (<10 mL/kg per min),

inability to walk at a normal pace for more than 3 min, reduced serum Na+ concentration (<133 mEq/L),

reduced serum K+ (<3 meq/L), total potassium stores elevated (>500 pg/mL) BNP, ANP

↑ Plasma norepinephrine, renin, arginine vasopressin aldosterone, angiotensin II,

↑ endothelin-1 ↑ interleukin-6

Markers of oxidative stress, oxidized low-density lipoprotein serum uric acid, lower hemoglobin