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CONGESTIVE HEART FAILURE:

A PATH FROM

CONVENTIONAL TO ADVANCE THERAPY

PRESENTED BY

MOMIN ALTAMASH

M PHARM 1 ST YEAR

(PHARMACOLOGY)

ROLL NO. 22

GUIDED BY

http://www.freewebs.com MR VINOD GUPTA

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Table of Contents :

1. INTRODUCTION

2. PATHOPHYSIOLOGY

3. PHARMACOLOGICAL TREATMENT OF CONGESTIVE HEART FAILURE

4. NEWER DRUGS UNDER RESEARCH

5. ADVANCES IN THE TREATMENT

6. NON PHARMACOLOGICAL TREATMENT

7. CONCLUSION

8. REFRENCES

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1 ) Introduction :

CONGESTIVE HEART FAILURE

Factors that may produce congestive heart failure

Obstruction Insufficiency Raised pressure

Inflammation Oxygen lack Toxins

Malnutrition Anaemia Hyperthyroidism

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SYMPTOMS

• http:/www.nationdisease.com

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2) Pathophysiology of Congestive Heart Failure :

• Congestive heart failure is the pathophysiologic state in which –

• the heart is unable to pump blood at a rate commensurate with the requirements of metabolizing tissues, or can do so only from an elevated filling pressure (Braunwald and Bristow, 2000).

• Heart failure is a complex of symptoms –

• That is fatigue, shortness of breath, and congestion that are related to the inadequate perfusion of tissue during exertion and often to the retention of fluid. Its primary cause is an impairment of the heart's ability to fill or empty the left ventricle properly (Cohn, 1996).

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John Burton, MD- Albany Medical Center-Albany, New York

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Preload is a passive stretching force exerted on the ventricular muscle at the end of diastole. Preload is caused by the volume of blood in the ventricle at the end of diastole.

Afterload is the force resisting the contraction of the cardiac muscle fibers. Afterload can also be considered as the blood pressure exerted on the Atrial Valve during diastole

Contractility refers to the ability of cardiac muscle fibers to shorten when stimulated (strengthJohn Burton,

MD- Albany Medical Center-Albany, New York

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PUMP FAILS

STROKE VOLUME

COMPENSATORY MECHANISMS

SNS STIMULATION

MYOCARDIAL HYPERTROPHY

HORMONE RELEASE

EPINEPHRINE/NOR

EPINEPHRINE

WALLS THICKEN

RENIN

ANGIOTENSIN 1 ANGIOTENSIN 2

ALDOSTERONE

PERIPHERAL VASOCONSTRICTION

AFTERLOAD

CONTRACTILITYHEART RATE

PATHOPHYSIOLOGY

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• Compensatory mechanisms may restore CO to near-normal.

• But, if excessive the compensatory mechanisms can worsen heart failure because . . .

• Vasoconstriction: ↑’s the resistance against which heart has to pump (i.e., ↑’s afterload), and may therefore ↓ CO

• Na and water retention: ↑’s fluid volume, which ↑’s preload. If too much “stretch” ↓ strength of contraction and ↓’s CO

• Excessive tachycardia → ↓’d diastolic filling time → ↓’d ventricular filling → ↓’d SV and CO

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3) PHARMACOLOGICAL TREATMENT

CONGESTIVE OF HEART FAILURE :

Drug Classes Used To Treat

CHF :

Cardiac Glycosides (ACE Inhibitors)

and AT1 Receptor Antagonists

Diuretics

Vasodilators

Aldosterone Antagonists

β blockers

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3.1] The Cardiac Glycosides (Cardenolides):

• Drug Members :

i. Digitoxin (Crystodigin)

ii. Digoxin (Lanoxin)

iii. Deslanoside (Cedilanid-D)

• Mechanisms of Action :

http://cvpharmacology.com

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• The net effect of the glycosides on the heart is as follows :

a. heart rate is slowed

b. contraction is greater due to increased filling volumes

c. ejection fraction is improved

d. increased ejection velocity

• Adverse Side Effects Of The Glycosides :

Fatigue, delirium, anorexia, headaches, hallucinations.

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3.2] Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors) and AT1 Receptor Antagonists:

• Drug Members:

• Captopril (Capoten)

• Enalapril (Vasotec)

• Lisinopril (Prinivil)

Mechanism:

• AT1 receptor antagonists should

at present be viewed as the preferred

alternative when ACE inhibitors cannot be tolerated

http://www.uspharmacist.com

• Adverse Side Effects : GI distress, dizziness, skin rashes, hypotension

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3.3) BETA-BLOCKERS:

http://www.cardiachealth.org

Beta-blockers may work by slowing the heart rate, which allows the left ventricle (the main pumping chamber of the heart) to fill more completely.

some of these medicines may also help open or widen blood vessels in the body. this makes them especially useful in some people with certain forms of heart failure who may also have high blood pressure

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3.4] Diuretics :

Classes of Diuretics

High Ceiling Loop Diuretics

Furosemide (Lasix) 20,40 & 80 mg

Ethacrynic Acid (Edecrin)

Bumetanide (Bumex)

Benzothiadiazide Diuretics

Hydrochlorothiazide (Hydrodiuril)

Clorthalidone (Hygroton)

Chlorothiazide (Diuril)10-20mg/kg

Potassium Sparing Diuretics

Triamterene (Dyrenium)

Amiloride (Midamor)

spironolactone (Aldactone)100-200mg

Osmotic Diuretics

Mannitol (Osmitrol)

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http://pharmacologycorner.com

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• Side effects

• Low plasma ion concentrations :

• Hypokalemia (low blood Potassium)

• Hyponatremia (low blood Sodium)

• Hypocalcemia (low blood Calcium)

• Hypomagnesemia (low blood Magnesium

• diarrhoea,

• drowsiness,

• headaches,

• impotence,

• mental confusion

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4) NEWER DRUGS UNDER RESEARCH 

• 4.1) Coenzyme Q10 :

•   occurs naturally in the body and is essential to survival.

• Acts as an electron carrier in the mitochondria, http://www.netrition.com

• CoQ10 levels are decreased in the heart muscle of patients with heart failure,

• Double blind controlled trials have shown that CoQ10 improves symptoms, functional capacity and quality of life in patients with heart failure with no side effects

• "Other heart failure medications block rather than enhance cellular processes and may have side effects.

• Supplementation with CoQ10, which is a natural and safe

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• It corrects a deficiency in the body and blocks the vicious metabolic cycle in chronic heart failure called the energy starved heart.“

•  sources-Q10 is present in food, including red meat, plants and fish, but levels are insufficient to impact on heart failure.

• CoQ10 is also sold over the counter as a food supplement.

• Coenzyme Q10 decreases all cause mortality by half.

• It is the first drug to improve heart failure mortality in over a decade and can be added to standard treatment. 

http://www.vitacost.com

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•4.2) Bromodomain and extraterminal domain (BET) protein inhibitors :

Current therapies are not adequately effective at improving health and preventing deaths.

Bromodomain and extraterminal domain (BET) proteins activates genes that contribute to heart failure. 

Heart failure may be triggered by the activation of a large set of genes that cause the walls of the heart to thicken and develop scar tissue, impairing the organ's ability to pump blood normally.

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BET proteins can have a huge impact on gene activity because they belong to a class of molecules called epigenetic readers, which recognize special marks on DNAprotein complexes and attract gene-activating proteins to those spots.

BET inhibitor called JQ1 shows promise in treating heart failure. JQ1 protect against heart-wall thickening, the formation of scar tissue, and pump failure

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5)

Advances in treatment of

CHF

Stem cell therapy Gene therapy

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5.1) Stem cell therapy.

• Stem cells - These are undifferentiated cells that can differentiate into specialized cell types. stem cells come from 3 main sources:

i. Embryonic stem cells,

ii. Adult tissue (adult stem cells).

iii. Endometrial stem cells.

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Adult stem cells

Exist throughout the body after embryonic development. found in tissues such as the brain, bone marrow, blood, blood vessels, skeletal muscles, skin, and the liver.

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Embryionic stem cells

Derived from a four- or five-day-old human embryo that is in the blastocyst phase of development. in IVF (in vitro fertilization) clinics there are extra embryos. only one is implanted into a woman from several eggs fertilized in a test tube.

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Endometrial stem cells

It involves extraction of a small amount of menstrual blood from young healthy donors that is called as endometrial stem cells.

CLASSIFICATION

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Fig: pictorial representation of injecting stem cells in cardiac tissue

http:/www.trialx.com

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• Possible mechanisms of recovery include:

• Generation of heart muscle cells,

• Stimulation of growth of new blood vessels to repopulate damaged heart tissue,

• Secretion of growth factors,

• Assistance via some other mechanism,

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• PROCEDURE OF STEM CELL THERAPY

1. COLLECTION 2. PROCESSING AND 3. INFUSION 4. ENGRAFMENT CRYOPRESRVATION AND RECOVERY

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5.2) GENE THERAPY :

• Gene therapy is the use of DNA as a pharmaceutical agent to treat disease. Gene therapy is a technique that uses genes to treat or prevent disease.

• Researchers are testing several approaches to gene therapy, including:

• Replacing a mutated gene that causes disease with a healthy copy of the gene.

• Inactivating, or “knocking out,” a mutated gene that is functioning improperly.

• Introducing a new gene into the body to help fight a disease.

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http:/www.wikipedia.org

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• SARCOENDOPLASMIC RETICULUM (SER):

• Sarcoplasmic reticulum activated by Ca2+ leads to contraction.

• In heart failure, decrease expression of Ca2+ causes impairment of SER.

• widely used viruses for gene delivery to heart are recombinant AAVs (adeno associated virus).They are relatively sective for cardiac myocites

• There is high diastolic and low systolic Ca2+ levels when SER is impaired.

Studies has shown that by increasing SER Ca2+ expression by viral transduction of SER Ca2+ transgene, heart failure can be treated .

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• OTHER TARGETS

a) PHOSPHOLAMBAN:

• It is a protein that regulates the calcium pump in cardiac muscle.

• This protein is a potent inhibitor of sarcoplasmic reticulum ca2+ ATPase in unphosphorylated state, but inhibition is relieved upon phosphorylation.

• Inhibitory phospholamban, antisense and psuedophosphorylated state mutant is used in heart failure by viral delivery.

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b) ADENYLYL CYCLASE 6

protein kinase a phosphorylates phospholamban and SERCA2A activity is enhanced.

Symptoms of heart failure is alleviated by viral delivery of AC6 transgene as result of SERCA2a function.

FIG: ROLE OF ADENYLYL CYCLASE (AC6) IN HEART CONTRACTION

http:/www.sciencedirect.com

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c) PROTEIN PHOSPHATASE 1

• It is involved in the regulation of a variety of cellular processes,.

• Increased PP1 activity has been observed in the end stage of heart failure 

• SR ca2+ upake is suppressed by the (ppi) because it dephosphorylates the phospholamban.

• Pp1 is reduced using (sh)RNA and has showed improved cardiac function and reduced interstitial fibrosis in mouse model of heart failure.

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d) SMALL UBIQUITINE LIKE MODIFIER (SUMO 1 ) :

• SUMO 1 is a key component in cardiac function .

• The interaction between SUMO 1 and SERCA2A is crucial for regulating calcium levels inside cardiac myocytes.

• Reduction in SUMO 1 protein reduces SERCa2+, and thus efficient calcium handling in patients with failing hearts .

• Introduction of SUMO 1 through gene therapy is associated with improved activity of SERCA2A, which resulted in improved cardiac function through an augmentation of cardiac contractility.

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FIG : GENE THERAPY PROCEDURE

http://www.trip2medi.com

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• GENE DELIVERY METHODS ;

A) Transvascular intracoronary antegrade and retrograde delivery :

B) Direct intramyocardial delivery :

http://www.sciencedirect.com

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6) Device therapy :

• Damage to the heart muscle can cause changes in the electrical system of the heart.

• There are three different types of devices that can be used in the treatment of heart failure to correct an abnormal heartbeat. 

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I. Pacemakers :

• The traditional pacemaker has two parts: lead wires and a pulse generator, which houses a battery and a tiny computer.

• The lead wires sense the heart's electrical activity, and when the computer determines that the heart rhythm is off, it responds by sending electrical impulses to the heart muscle to correct its rate.

• Pacemakers are usually used to treat heart rhythms that are too slow. But they can also be used to treat fast rhythms or to increase the heart rate in response to changes in the patient's activity level

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2. Biventricular

(cardiac resynchronisation therapy) :

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3) Internal cardioverter defibrillator (ICD):

ICD senses electrical activity and sends a shock to the heart if it detects a dangerous heart rhythm implantable cardiac defibrillators reduce the risk of death from sudden cardiac arrest by 23 percent in patients with heart failure

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• Continuous positive airway pressure(CPAP):

• To improve the prognosis of CHF, additional novel approaches to its therapy are required. One promising approach is the use of continuous positive airway pressure (CPAP ).

• When applied via a nasal mask, CPAP provides a noninvasive mechanical assist to the failing heart by increasing intrathoracic pressure and augmenting stroke volume and cardiac output,CPAP improves the mechanical efficiency of the failing heart  possibly through reverse ventricular remodeling.

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7) Conclusion

Heart failure is a major health issue with a high rate ofmorbidity and mortality

Thus, there is a substantial need for new strategies toprevent the progression of heart failure.

Until now, heartfailure was seen as an incurable disease.

However, genetherapy approach have offered the promise of an effectivetherapy for reversing systolic heart failure

Great advances in understanding the pathobiologyof HF and their application to further improvements of patient care are withun reach

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Time will tell whether a single targetapproach is sufficient to restore heart function and preventdeterioration or whether multiple gene targets are neededalong with stem cell therapy to eventually replace theinjured myocardium.

Using a viral-delivery gene therapyapproach to treat heart failure by enhancing contractility isnot yet a reality, but substantial progress in that directionhas been made in the last few years.

Great advances in understanding the pathobiologyof HF and their application to further improvements of patient care are within reach

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• Refrences

• 1. Beltrami, A.P., Urbanek, K., Kajstura, J., Yan, S.M., Finato, N., Bussani, R., Nadal-Ginard, B., Silvestri, F., Leri, A.,

Beltrami, C.A., and Anversa, P. (2001). Evidence that human cardiac myocytes divide after myocardial infarction. N. Engl. J. Med. 344, 1750–1757.

• 2 . Itskovitz-Eldor, J., Schuldiner, M., Karsenti, D., Eden, A., Yanuka, O., Amit, M., Soreq, H., and Benvenisty, N. (2000).

Differentiation of human embryonic stem cells into embryoid bodies comprising the three embryonic germ layers. Mol. Med.

6, 88–95.

• 3. Jackson, K.A., Majka, S.M., Wang, H., Pocius, J., Hartley, C.J., Majesky, M.W., Entman, M.L., Michael, L.H., Hirschi, K.K.,

and Goodell, M.A. (2001). Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin.

Invest. 107, 1–8.

• 4. Kehat, I., Kenyagin-Karsenti, D., Druckmann, M., Segev, H., Amit, M., Gepstein, A., Livne, E., Binah, O., Itskovitz-Eldor,

J., and Gepstein, L. (2001). Human embryonic stem cells can differentiate into myocytes portraying cardiomyocytic

structural and functional properties. J. Clin. Invest. (in press)

• 5. Kessler, P.D. and Byrne, B.J. (1999). Myoblast cell grafting into heart muscle: cellular biology and potential applications.

Annu. Rev. Physiol. 61, 219–242.

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