Lowoutput cardiac failure

PATHOPHYSIOLOGICAL BASIS OF HEMODYNAMICS OF LOW OUTPUT HEART

FAILURE

Aniruddha Mandal

Chair personDr. Dipankar Ghosh

Dastidar

Heart failure (HF) is a clinical syndrome that occurs in patients who, because of an inherited or acquired abnormality of cardiac structure and/or function, develop a constellation of clinical symptoms (dyspnea and fatigue) and signs (edema and rales) that lead to frequent hospitalizations, a poor quality of life, and a shortened life expectancy

DEFINITION

CARDIAC OUTPUT ( C O.): Quantity of blood pumped into the aorta each minute by the heart

STROKE VOLUME × HEART RATE

DEPENDS DIRECTLY ON :(1) body metabolism

(2) exercise

(3) age

(4) Body surface area.

CARDIAC INDEX : C O. / BODY SURFACE AREA

Cardiac Output =

Arterial Pressure / Total Peripheral Resistance

Normally resistence is sum of Blood Flow Regulation in All the Local Tissues

Two primary factors in cardiac output regulation:

(1)cardiac pumping capacity

(2)venous return

CARDIAC FACTOR CONTROL OF CARDIAC OUTPUT

HYPOEFFECTIVE HEART

Myocardial ischemia & infarction

Myocarditis

Cardiac metabolic derangement

Cardiac tamponade

Arrythmia

Severe valvular heart disease

Congenital heart disease

DETERMINANT OF VENOUS RETURN

Mean systemic filling pressure (psf) --Degree of filling of the systemic circulation

Right atrial pressure----backward force

Resistance to blood flow

VENOUS RETURN – DETERMINATION OF CO.

INCREASED IN

↑ BLOOD VOLUME

↑ SYMPATHETIC ACTIVITY DUE TO CONSTRICTION OF

Capacitance vessels

Pulomonary vessels

Heart chambers

arteriole

MEAN SYSTEMIC FILLING PRESSSURE

VENOUS RETURN = CARDIAC OUTPUT

NERVOUS & REFLEX CONTROL OF OUTPUT

Sympathetic stimulation→effect 0n

heart ↑Na+ ,H2O absorption-

kidney

↓ renal blood flow

↑AVP,RAS

↑ 𝑝𝑠𝑓.

Immediate activation of REFLEXEES

Baro ChemoBrain

ischemiaHeart

damage

Heart suddenly severely damaged

↓ CO.Damming of blood in

vein

Spectrum of acute heart failure

Reflex get blunted in 2-3 days. SEMICHRONIC STAGE ensues→

Kidney fluid

retention

↑ psf

Distended vein→

↓ venous resistence

Progressive recovery of heart

Reperfusin, compensatory hypertrophy,collateral,

Acute heart failure

compensated

With Sympathetic

support

After someday symp. Support

not needed

Decompensated

Massive myocyte loss,

Overstretching,

Heart muscle edema,

PROGRESSION

CARDIORENAL MODEL- excessive salt and water retention caused by abnormalities of renal blood flow

CARDIOCIRCULATORY OR HEMODYNAMIC MODEL-abnormal pumping capacity of the heart

- not adequately explain relentleess progress

PROGRESSIVE MODEL - primary determinant

neurohumoral activation

left ventricular remodeling

CHRONIC HEART FAILURE AS A PROGRESSIVE MODEL

Activation of the Sympathetic (Adrenergic)

Nervous System

Increased circulating Norepinephrine (NE)-2-3 times

Heart extracts NE from the arterial blood & also synthesized in myocardium.

With progression cardiac depletion of NE-“exhaustion” phenomenon

↓ myocardial tyrosine hydrxylase

↓ NE uptake

NEUROHUMORAL MECHANISM

β- adrenergic desensitization

Activated comparatively later by

1. Renal hypoperfusion

2. ↓ Na delivery to macula densa

3. Sympathetic stimulation

Angiotensin receptor- G protein coupled -2 types

AT1 –vasoconstriction, cell growth, aldosterone and catecholamine release-

AT2 –vasodilation, inhibition of cell growth, natriuresis, and bradykinin release-

Activation of the Renin-Angiotensin System

s

ANGIOTENSIN ĪĪ- short term circulatory support.

↑ Na+, water, absorption, thirst, AVP , aldosteron

↑ NE secretion

induce fibrosis

ALDOSTERONE

Effects on MYOCARDIUM & VASCULATURE causing

fibrosis & hypertrophy → ↓ 𝑐𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 & ↑ 𝑠𝑡𝑖𝑓𝑓𝑛𝑒𝑠𝑠

Endothelial dysfunction

Baroreceptor dysfunction

↓NE uptake

Oxidative stress → inflammation in target tissue

Cont.. RAAS

REACTIVE O2 SPECIES (ROS) ACTIVITY ↑ due to :

Mechanical strain

Neurohormone

Inflammatory cytokine

↓ NOS activity

EFFECT :

Hypertrophy

Reexpression of fetal gene programme

Fibroblast proliferration→↑ collagen, MMP

↓ bioavailability of NO in peripheral vasculature

OXIDATIVE STRESS(ROS)

Neurohormonal Alterations of Renal Function

VASODILATTORY PROSTAGLANDIN: PGE2, PGI2

NO, bradykinin, adrenomedullin, apelin

NATRIURETIC PEPTIDES : ANP, BNP, CNP, DNP, urodilantin

Renal effects become blunted with advancing HF

COUNTER REGULATORY NEUROHORMONE

ANP secreted in short burst in ACUTE changes

BNP regulated transcriptionally as CHRONIC response

PROHORMON cleaved to large biologically inactive N-terminal fragments (NT-ANP or NT-

BNP)

smaller biologically active peptides (ANP or BNP)

degraded by neutral endopeptidase

Degraded by NEUTRAL ENDOPEPTIDASE & VASOPEPTIDASE

Candoxatrilat endopeptidase inhibitor

Omapatrilat inhibits both neutral endopeptidase and ACE

NATRIURETIC PEPTIDES

Neurohormonal Alterations in the PERIPHERAL VASCULATURE

Secretion enhanced by

Vasoactive agent (NE, angiotensin, thrombin)

Cytokines

EFFECT

Vasoconstriction

cell proliferation

pathologic hypertrophy

Fibrosis

Increased contractility

↑ Pulmonary artery pressure, resistence

ENDOTHELIN

NEUROPEPTIDE Y released together with NE & inhibit NE secretion--- blunted in HF

UROTENSIN İİ :

most potent endogenous cardiostimulatory peptide identified thus far

Trophic & mitogenic to vascular smooth muscle, myocyte, fibroblast

Bradykinin, Aplein, Adrenomedullin- offseting vasoconstriction, antidiuresis, hypertrophy

Disrupted subcellular location of NOS

↓ NOS3 in HF

Nitroso redox imbalance–unopposed activity of xanthin oxidase (↓NOS1)

Remodeling ↓ in NOS2 deficiency

NITRIC OXIDE

TNF, PAI-1, TGF-β, resistin and-

Leptin : hypertension, hypertrophy, ↑ in HF of obese patient

ADIPONECTIN ↓ infarct size, apoptosis

it ↓ in hear failure

ADIPOKINES

INFLAMMATORY( IL-6, TNF) & ANTIINFLAMMATORY(IL-10) IMBALANCE

Traditionally described in anatomical term

BUT there is also alteration in

A. Biology of cardiac myocyte

B. Volume of myocyte & nonmyocyte component

C. Geometry & architecture of ventricular chamber

LEFT VENTRICULAR REMODELING

Alterations in the BIOLOGY CARDIAC MYOCYTE HYPERTROPHY

Alterations in Excitation-Contraction Coupling

↓ SERCA2

↓phospholamban phosphorylation;

Leakage of Ryanodine

receptor(hyperphsphorylation)

phosphorylation& dysfunction of L –

type Ca++ cnl.

Ca++ entry in reverse mode by

Na+/Ca++ exchanger.

Slower delivery of ca++ to contractile

apparatus & slow fall in diastole;

change in abundance/

phosphorylation in regulatory

protein

Abnormal prolongation

of A.P.

↓ force of CONTRACTION

& RELAXATION

Cont..

Shift to fetal gene program – fetal isoform of myosin heavy chain(MHC; α →β)

↓ Myofibrilar ATPase & Myosin ATPase Myocytolysis – proteolysis of myofilament

Alteration in myofilament regulatory protein Altered activity of Myosin light chain ; troponin

tropomyosin complex

CYTOSKELETAL PROTEIN (actin, desmin, dystrophin, vinculin) altered expression

Abnormalities in Contractile and Regulatory Proteins

NECROSIS : Directly from ischemia, myocardial injury, toxin, infection

From Neuroheumoral activation

APOPTOSIS : induced by catecholamines acting through beta1-adrenergic receptor

angiotensin II

ROS, NO, inflammatory cytokines

mechanical strain

AUTOPHAGY:sequestering organelles and proteins in a double-membrane vesicle inside the cell (autophagosome) → subsequently delivered to the lysosome for degradation

Alterations in the Myocardium in Heart Failure

Type I and type III collagen ensures

Structural integrity of adjoining myocytes

Interaction of collagen and integrins with the cytoskeletal proteins --maintainin alignment of myofibrils

Phenotypic conversion to myofibroblast

↑ collagen synthesis & ↑ MMP → ↑ Turnover

Replacement fibrosis

FIBROBLAST

Alterations in the Left Ventricular Structure & Geometry in Heart Failure

EXTERNAL PRESSURE & CO.

HEART FAILURE

WITH PRESERVED

EJECTIONFRACTION

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