Physiological Basis Of Treatments Of Heart Failure Biology Essay

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Heart failure is a clinical complex syndrome of symptoms and signs resulting from any structural or functional cardiac disorder. Untreated it has a poor prognosis, but this can be improved considerably with early and optimal treatment.(1) The most common causes of heart failure in our country is coronary artery disease (CAD) and non-ischemic causes of systolic dysfunction and may have an identifiable cause (e.g., hypertension (HT), valvular disease, myocardial toxins, or myocarditis) or may have no prominent cause (e.g., idiopathic dilated cardiomyopathy).Patients with HF are almost equally divided into those with impairment of left ventricular blood ejection (systolic dysfunction) those with preserved ejection fraction(EF) and impairment of the tendency of the ventricle to fill with (diastolic dysfunction). The result of either type of HF is decreased cardiac output (CO). Less blood is pumped from the heart to the body. Decreased CO also can lead to decreased blood pressure (BP). Although the systolic function is reduced or not, most of the current evidence on drug treatment is for HF due to left ventricular systolic dysfunction. The cardiac manifestations of HF are dyspnea and fatigue, which may reduce exercise ability, and fluid accumulation, which may cause to pulmonary (fluid backing up in the lungs) and peripheral edema. The classification system that is most commonly used to quantify the amount of functional limitation assumed by HF is presented. This system divide patients to 1 of 4 functional classes depending on the degree of effort needed to elicit symptoms, only at levels that would limit normal individuals (class I), on ordinary exertion (class II), on less-than-ordinary exertion (class III), patients might have features of HF at rest (class IV). But functional classification reflects the subjective assessment of physician and patient.(1,2) The principal manifestation of the HF such progression is a process known as remodeling which occurs as a homeostatic attempt to decrease wall stress, through increases in wall thickness. This ultimately results in a change in the geometry of the left ventricle (LV) such that the chamber dilates, hypertrophies, and becomes more spherical. The process of cardiac remodeling generally precedes the development of symptoms. The process of remodeling continues after the appearance of symptoms and may contribute importantly to worsening of symptoms despite treatment. Heart failure is a very common disease that can have a high death rate. Despite advancements in treatment, the death rate has been increasing. Therefore, understanding the disease mechanism and its progression, common causes, risk factors, signs and symptoms, and treatments are very important.

DEFINITION

A state in which heart fails to maintain an adequate circulation (CO) for the needs of body, despite a satisfactory venous filling (VF) pressure.( by definition excludes those condition in which the CO is low due to decreased venous filling pressure like in hypo volaemic shock condition)

Classifications

Acute and chronic HF

Left ventricular, right ventricular & biventricular(congestive) HF

HF due to Systolic dysfunction & Diastolic dysfunction

Forward failure & Back ward failure

High output failure & Low output failure(1)

The New York Heart Association (NYHA) classification is the most widely used

Stratification tool for assigning patients with CHF to functional classes

Class I No limitation of activities

Class II Slight, mild limitation of activity

Class III Marked limitation of activity

Class IV Activity severely limited(1,3,8)

Stages

Stage A

This stage identifies patient who has high adventure for developing HF, since they have one or more risk factors, but they do not have structural disorders of the heart.(1)

Stage B

This stage refers to patients who, despite a structural disorder of the heart, have never developed symptoms of HF. (1)

Stage C

This stage shows patients with past or current features of HF (1)

Stage D

This stage shows patients with late-stage disease who need special treatment strategies like mechanical circulatory help, continuous inotropic infusions. (1)

PATHOPHYSIOLOGY

When the HF, considerable changes occur to the heart and peripheral vascular system in response to the haemodynamic changes associated with HF .These physiological changes are compensatory and maintain CO and peripheral perfusion.(8) However, as HF progresses, these mechanisms are overwhelmed and become pathophysiological. The development of pathological peripheral vasoconstriction and sodium retention in heart failure by activation of the renin-angiotensin-aldosterone system are a loss of beneficial compensatory mechanisms and represent cardiac decompensation.(10) Factors involved are venous return, outflow resistance, contractility of the myocardium, and salt and water retention.(11)

Causes of heart failure

1. Main causes

Ischaemic heart disease (35-40%)

Cardiomyopathy (dilated) (30-34%)

Hypertension (15-20%) (7)

2.Other causes,

Cardiomyopathy

Hypertrophic or obstructive

Restrictive (amyloidosis, sarcoidosis)(7)

Valvular heart disease

Mitral stenosis & regurgitation

Aortic stenosis & regurgitation

Tricuspid stenosis & regurgitation(7)

Congenital heart disease

Atrial septal defect (ASD)

Ventricular septal defect (VSD) (7)

Alcohol and drugs

Chemotherapy(imatinib, trastuzamab)

Hyperdynamic circulation

Anaemia

Thyrotoxicosis

Haemochromatosis

Paget's disease(7)

Right heart failure

RV infarct,

Pulmonary hypertension,

Pulmonary embolism,

cor pulmonale (COPD)

(HF can involve primarily the right ventricle)(7)

Tricuspid incompetence

Arrhythmias

atrial fibrillation

Ventricular fibrillation & flutter

bradycardia

complete heart block

the sick sinus syndrome(7)

Pericardial disease

constrictive pericarditis

pericardial effusion

Infections

Pathophysiological changes in HF are seen,

Altered myosin gene expression

Decreased myosin ATP activity

Changes in isoforms of myosin

Abnormal actin & tropomyosin synthesis

Decreased beta adrenergic receptors on myocardium(7)

Altered sarcoplasmic Ca2+ -ATPase density

Slow relaxation of myocardium & it contri bute to diastolic dysfunction(7)

Increased atrial natriuretic peptide (ANP) secretion

Increased collagen synthesis

Myocyte hypertrophy

This is due to high work load

This is adaptive mechanism.

Peripheral vasoconstriction

This is due to sympathetic activity.

Salt and water retention

This is due to reduced renal perfusion

Sympathetic stimulation

Ventricular dilatation(7)

Physiological factors affecting CO are very important in HF,

Heart rate(HR) :

autonomic nervous system

hormonal(humoral) control (7)

Stroke volume(SV):

Preload

Contractility

afterload(7)

Preload (Venous return)(VR)

Stretching the myocardial fibers during diastole is the preload (end diastolic stretching). (3)End diastolic volume (EDV) or end diastolic venous filling pressure affect on preload. Failure of myocardium leads to a reduction of the volume of blood ejected with each heartbeat and an increase in the volume of blood remaining after systole. (7)This increased EDV stretches the myocardial fibers. (10)

Afterload (Outflow resistance)

It can be expressed as tension which is developed in the wall of ventricles during systole to open the semilunar valves and ejection of blood to aorta & pulmonary arteries in both sides of heart. (7) According to Laplace law so,

Increased afterload is due to

elevation of arterial resistance

increased ventricular size

myocardial hypotrophy

Decreased afterload is due

decreased arterial resistance

myocardial hypertrophy

decreased ventricular size(7)

An increase in afterload decreases the cardiac output. This results in a further increase of EDV and dilatation of the ventricle itself, which further arouse the problem of afterload. This is expressed by, (5)

Laplace's law: the tension of the myocardium (T) is proportional to the intraventricular pressure (P) multiplied by the radius of the ventricular chamber.

Myocardial contractility

Changes in ability of myocardium to develop the force of contraction that occur independently on the changes in myocardial fibre length. The sympathetic nervous system is activated in heart failure via baroreceptors as an early compensatory mechanism, which provides inotropic support and maintains cardiac output. (4) Chronic sympathetic activation, however, has harmful effects by further increasing neurohormonal activation and myocyte apoptosis. This is compensated by a down regulation of β-receptors. (7)

Factors involved in contractile state of myocardium,

Circulating catecholamines

Digitalis & other inotropic effects

Loss of myocardium

Sympathetic & parasympathetic nerve impulses

Hypoxia, Hypercapnea, Acidosis(7)

Pharmacological depressant

Force-frequency relation(7)

Myocardial remodeling in heart failure

LV remodelling is a process of progressive alteration of ventricular shape, size and function owing to the impact of neurohormonal, mechanical and possibly genetic factors in several clinical conditions, including myocardial infarction (MI), cardiomyopathy, HT, and valvular heart disease.(9) Its include hypertrophy, loss of myocytes, and increased interstitial fibrosis. Remodelling continues for months after the initial insult, and the ultimate change in the shape of the ventricle becomes responsible for significant impairment of overall function of the heart as a pump. In cardiomyopathy, the process of progressive ventricular dilatation or hypertrophy occurs without ischemic myocardial injury or infarction. (10)

CLINICAL SYNDROMES OF HEART FAILURE

There are many clinical syndromes are go with HF,

Congestive HF

Left HF

Right HF

Systolic HF

Forward failure theory

Back ward failure theory

Diastolic HF

High-output HF

Acute HF

Chronic HF(7)

Left heart failure

Causes,

Ischaemic heart disease(IHD) (the most common reason)

Systemic hypertension (chronic)

Mitral and Aortic valve disease-

( Mitral stenosis causes left atrial hypertension)

Cardiomyopathies. (7)

Clinical relevant,

1. Symptoms

Fatigue

exertional dyspnea

orthopnea

paroxysmal nocturnal dyspnoea

2. Signs

Cardiomegaly

Auscultation detects a left ventricular third or fourth heart sound

Tachycardia (gallop rhythm)

Mitral regurgitation(MR)

Crackles are heard at the lung bases

Pulmonary oedema(7)

Right heart failure

Causes,

Chronic lung disease (cor pulmonale)

Isolated right ventricular cardiomyopathy

Left HF

Left-to-right shunts (ASD,VSD)

Mitral valve disease with pulmonary hypertension

Pulmonary embolism or pulmonary hypertension

Pulmonary valve disease

Tricuspid valve disease (7)

Clinical relevant,

Symptoms,

Fatigue

Breathlessness

Anorexia

Nausea(7)

Signs

Dependent pitting oedema

free abdominal fluids are produced (ascites)

Jugular venous distension (plus or minus v waves of tricuspid regurgitation)

Pleural transudates (right plura)

Cardiomegaly(7)

Congestive HF

All most all HF are congestive heart failure. (2) This is due to diseases affecting both ventricles. Long lasting left ventricular failure causes to right ventricular failure resulting congestive HF. (8) Congestive heart failure is a syndrome that can be caused by multiple underlying diseases

Congenital heart disease

Atherosclerosis

Cardiomyopathy

Chronic rapid heart beat

Diabetes

HT

Left or right-sided failure

Previous MI

Prolonged alcoholism

Rheumatic fever

Valve disorders

Ventricular failure(7)

Symptoms,

1.Involve in gravity:

Ankles oedema

Orthopnea (shortness of breath when lying down position)

Shortness of breath during exertion(7)

2. Involving circulation

Peripheral Cyanosis(5)

Fatigue or weakness

Rapid or irregular heart beat

Changes of behavior (restlessness, confusion, and decreased attention span) (7)

Systolic HF

Systolic ventricular failure is most commonly due to,

CAD

MI

The left ventricle is normally dilated and fails to contract normally.

Forward failure theory, this due to inadequate CO at rest or with exercise stress results in decreased perfusion to vital organs.

Symptoms,

Anorexia

Dizziness

Fatigue

Nausea

Poor mentation

Weakness

Signs,

Cold extremities

Hypotension

Pallor

Tachycardia(7)

Back ward failure theory, This due to decreased contractility results in increased LV diastolic pressure causing fluid buildup in the pulmonary vasculature.

Symptoms,

Abdominal fullness

Dyspnea

Leg swelling

Orthopnea

Signs,

Gallops (third heart sound)

Increased Jugular venous pressure

MR/TR murmurs

Peripheral edema

Riles(7)

Diastolic heart failure

Diastolic HF results from impaired relaxation of myocardium. Ventricular wall stiffness is increased and left ventricular compliance is decreased. This leads to impairment of diastolic ventricular filling and then CO is decreased. CAD, HT and hypertrophic cardiomyopathy are common causes. Amyloid may lead to diastolic dysfunction. (1)

High-output heart failure

The heart is unable to supply the conditions like anemia, beriberi, and thyrotoxicosis. (2) This HF is like low-output condition but is associated with tachycardia and a gallop rhythm. Patients are often warm with distended superficial veins. Unlike low-output failure, the oxygen content of systemic venous blood is high owing to the delivery of large amounts of arterial blood to non-metabolizing tissues. (7)

Chronic heart failure

Making an accurate diagnosis of HF and determining its cause can be difficult. Clinical diagnosis is confirmed to be accurate in approximately half of cases when investigated by echocardiography. The probability of HF in the presence of suggestive symptoms and signs is increased if there is a history of MI or angina, an abnormal ECG, or a chest X-ray showing pulmonary congestion or cardiomegaly. (9)

Symptoms

Decreased exercise tolerance

Orthopnoea ankle swelling

Paroxysmal nocturnal dyspnea

Shortness of breath on exertion (10)

Acute Heart Failure

Acute HF is characteristic with acute (cardiogenic) dyspnoea characterized by signs which cause to pulmonary congestion. It is suitable to name as acute pulmonary edema or cardiogenic shock. (2)

Acute HFof the heart most commonly occurs in the setting of acute myocardial infarction when there is extensive loss of ventricular muscle. The condition may also occur with rupture of the interventricular septum producing a ventricular septal defect, or be due to acute valvular regurgitation.(5) Common examples of valvular regurgitation are papillary or chordal rupture producing mitral regurgitation, or sudden aortic valve regurgitation in infective endocarditis. Other causes of acute heart failure include obstruction of the circulation by acute pulmonary embolus and cardiac tamponade. In each case severe cardiac failure can occur with a relatively normal heart size. (7)

DIAGNOSIS OF HEART FAILURE

The diagnosis of HF depends on history and clinical information. It is wanted evidence of cardiac dysfunction with relevant investigation with the help of echocardiography.

Investigations are wanted to diagnose it, they are two types,

Diagnostic

Prognostic (7)

Diagnostic method,

Blood tests

Cardiac enzymes

Full blood count(FBC)

Liver investigations

Thyroid function

Urea and electrolytes imbalance

Cardiac biopsy.

Cardiac catheterization

Cardiac MRI.

Chest X-ray

Heart size

Pulmonary congestion checking(7)

Electrocardiogram

Arrhythmia

Hypertension

Ischaemia(7)

Echocardiography.

Amyloid

Cardiomyopathy

Ejection fraction

IHD

Intra cardiac thrombus.

Valve disease(7)

Natriuretic peptide

Nuclear cardiology

Radionuclide angiography (RNA)

Single photon emission computed tomography (SPECT)

Positron emission tomography (PET).

Stress echocardiography. (7)

Prognostic method,

Ambulatory (24-48 hours) ECG.

Cardiopulmonary exercise testing.

Resting and stress radionuclide angiography

TREATMENT OF HF AND THEIR PHYSIOLOGIC BASIS

Treatment is 2 divisions,

Normal life behavior advice

Drug treatments

Antiarrhythmic agents

Diuretics

Loop diuretic

Potassium-sparing diuretics

Thiazide diuretics

Inotropic agents

Digitalis glycosides

β-Adrenergic agonists(9)

Vasodilator therapy

Angiotensin receptor antagonists

Angiotensin-converting enzyme inhibitors (ACEI)

vasodilators of arterioles

Vasodilators

Î’-Adrenoceptor blocking agents(7)

Non-pharmacological treatment of HF

Normal life behavior advice

Diet control

Large meals are not suitable.

Weight reduction is wanted

Salt limitation is needed.

Alcohol is dangerous(because it has negative inotropic effect) (9)

Education

Counseling programs are important. Patient should be having knowledge about diet, drugs, and exercises.

Obesity control

Body mass index should be kept on normal level.

Physical activities & exercises

Sexual activity

Not suitable sildenafil like drugs which are include nitrates.

Smoking

Smoking should be stopped

Vaccination(7,8,9)

Drug management

Antiarrhythmic agents

Arrhythmias are frequent in HF and are implicated in sudden death. Although treatment of complex ventricular arrhythmias might be expected to

Improve survival, there is no evidence to support this and I may increase mortality. (10)

. Anticoagulants

Patients require prophylactic anticoagulation. HF is associated with a four-fold increase in the risk of a stroke.(10) Oral anticoagulants are recommended in patients with atrial fibrillation (AF) and in patients with sinus rhythm with a history of thromboembolism, left ventricular thrombus or aneurysm. In patients with known IHD,

antiplatelet therapy- (aspirin, clopidogrel)

statin therapy

Diuretics

Diuretics develop the renal excretion of salt and H2O by blocking tubular reabsorption of Na+ and Cl-. Fluid loss reduces ventricular filling pressures (preload) and produces certain haemodynamic and symptoms in patients with HF and also quickly develops dyspnoea and peripheral oedema. The intravenous administration of loop diuretics (furosemide) relieves pulmonary oedema quikly with the help of arteriolar vasodilatation reducing afterload. (7, 8)

Diuretics are many types,

Loop diuretic

Loop diuretics like bumetanide and furosemide have a quick onset of action. Concentrating power of the kidney is decreased. Loop diuresis also produces marked K+ loss and develops hyperuricaemia. (7)

Thiazide diuretics

Potassium excretion is put on. Thiazides are less effective in patients with reduced glomerular filtration rate (GFR). Thiazide diuretics together with loop diuretics have a higher diuretic effect. But their use may be complicated by over diuresis and electrolyte depletion. Consequence of complication,

ventricular arrhythmias

hyperkalaemia

hyperuricaemia

dyslipidaemia

E.g.; Bendroflumethiazide

Metolazone

Potassium-sparing diuretics

E.g.; Spironolactone

Amiloride triamterene (7)

Inotropic agents

Intravenous inotropes are always used to treat myocardial function in patients with acute left ventricular failure. Dobutamine, Dopexamine and Dopamine are intravenous adrenergic agonists. (7)

Digitalis glycosides

Digitalis glycosides have been used for many years in patients with HF and atrial fibrillation. A little increase in deaths inferred to be secondary to MI. So patients who are presented with severe HF despite therapy with vasodilators, diuretics should have digoxin. (2)It is partly protein-bound. Most of our excreted with urine. Its accumulation can occur in renal failure. It has positive inotrope effect Digoxin also improves baroreceptor responsiveness, and reduces sympathetic activity and circulating renin. Anorexia, nausea, altered vision are present in digoxine toxicity. Digoxin toxicity is treated by stopping the drug, restoration of serum potassium and management of arrhythmias. (7, 8, 9)

β-Adrenergic agonists

It depends on the representation that the inotropic state of the failing myocardium is impaired and that the myocardial response to adrenergic stimulation is reduced. Several adrenergic agonists have been examined in HF. These agents surely increase mortality. (7)

Vasodilator therapy

Diuretics and sodium restriction carry out to activate the renin-angiotensin system, stimulate formation of angiotensin. A difference of other neural and hormonal reactions serves to increase preload and afterload. These compensatory mechanisms are fruitful in supporting BP ,BF. Also HF reduces CO. The high venous pressures found in HF are also related to the activation of the sympathetic nervous system, arrival of circulating vasoconstrictors, shifting the Frank Starling curve to the right. (5, 10)

Angiotensin receptor antagonists

Angiotensin II receptor antagonists have equal hemodynamic effects to ACEI, where as they do not affect bradykinin metabolism.

E.g. Losartan

Ibersartan

candesartan

Valsartan (7)

Dilators of arterioles

Drugs like α-adrenergic blockers (prazosin) and direct smooth-muscle relaxants (e.g. hydralazine) are potent arteriolar vasodilators, where as they are not very effective in HF. Afterload is reduced by Calcium-channel blockers, but first-generation calcium antagonists (diltiazem, nifedipine) may have a baneful action on left ventricular function in HF.(10)

Angiotensin converting enzyme inhibitors

ACEI has lower systemic vascular resistance and venous pressure. It reduces levels of circulating catecholamines. The useful hemodynamic effect of these drugs represents to be independent of their inhibition of ACE. Some of these agents are pro-drugs (e.g. enalapril).These drugs have a delayed of action and first-dose hypotension may not occur.Pre drugs are better avoided if HF results in altered hepatic function. Engaged potassium-sparing diuretics should be discontinued .ACEI tend to raise potassium retention. A forthcoming examination is looking at dose and entity. (8, 9)

Vasodilators

glycerol trinitrate and isosorbide mononitrate act by decreasing preload and lowering venous pressure, with resulting reduction in pulmonary and dependent oedema. Reduction of filling pressure doesn't augment CO. (2) combination therapy of nitrate with hydralazine has been shown to develop mortality and exercise accomplishment, and may be salutary when ACEI are contra indicated. The advantage of vasodilators is not as great as with ACEI.

β-Adrenoceptor blocking agents

There is sufficient testimony to support the use of beta-blockers in patients with chronic HF. The non-selective vasodilator beta-blocker with additional vasodilator and antioxidant has demonstrated a significant progress in mortality. Following the administration of beta-blockers, the EF decline, whereas normally returns to base line. (7)Patients who have HF and already on treatment with a beta-blocker for a coexisting situation like CAD or HT. (11)

Non-pharmacological treatment of heart failure

Biventricular pacemaker

Patients with sinoatrial disease and atrioventricular conduction block are needed this. Pacemakers are also important in patients without AV block whereas with prolonged PR intervals. Biventricular pacing should also be considered in patients not responding to therapy in situations like systolic heart failure, optimal medical therapy, sinus rhythm, atrial fibrillation, mitral regurgitation. (7)

Cardiac transplantation

Cardiac transplantation has been the treatment for patients with severe intractable HF. The availability of heart transplantation is limited. Heart does not function usually. Cardiac denervation results in high resting HR. (9) loss of daily blood pressure variation and impaired renin-angiotensin-aldosterone system. The complications of heart transplantation are,

Allograft rejection

Allograft vascular diseases

Hypercholesterolemia

Hypertension

Infections

Malignancy(7)

There are specific contraindications to cardiac transplantation,

Alcohol or drug abuse

High pulmonary vasculature resistance

Severe renal or liver failure

Thromboembolism

Uncontrolled infection

Uncontrolled psychiatric illness

Left ventricular assist device and artificial heart

Left ventricular assist devices and artificial hearts are used to transplantation surgery. Mechanical devices are also mentioned if there is an ability of auto recovery.

Revascularization (2,7)

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