Congestive heart failure occurs when the heart is unable to pump enough blood to meet the body's needs. The document discusses the pathophysiology and various treatment approaches for congestive heart failure. Pharmacological treatments discussed include ACE inhibitors, beta-blockers, diuretics, and aldosterone antagonists. Newer potential treatments discussed are coenzyme Q10 and BET protein inhibitors. Non-pharmacological treatments discussed are stem cell therapy, gene therapy, cardiac devices like pacemakers, defibrillators and resynchronization therapy, as well as continuous positive airway pressure. The document concludes that while heart failure was once seen as incurable, new gene and stem cell therapies now offer promise for reversing syst

1. 1

2. 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
2

3. 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
3

4. 1 ) Introduction :
CONGESTIVE HEART FAILURE
Factors that may produce congestive heart failure
Obstruction
Inflammation
Malnutrition
Insufficiency
Oxygen lack
Anaemia
Raised pressure
Toxins
Hyperthyroidism
4

5. SYMPTOMS
•
http:/www.nationdisease.com
5

6. 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).
6

7. 7
John Burton, MD- Albany Medical Center-Albany, New York

8. 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
John Burton,
MD- Albany
Medical CenterAlbany, New
York
Contractility refers to the ability of cardiac muscle fibers to
shorten when stimulated (strength
8

9. PATHOPHYSIOLOGY
PUMP
FAILS
COMPENSATORY
MECHANISMS
STROKE
VOLUME
MYOCARDIAL
HYPERTROPHY
SNS
STIMULATION
EPINEPHRINE/
NOR
EPINEPHRINE
WALLS
THICKEN
RENIN
HORMONE
RELEASE
ANGIOTENSIN 1
ANGIOTENSIN 2
ALDOSTERONE
HEART
RATE
CONTRACTILITY
AFTERLOAD
PERIPHERAL
VASOCONSTRICTION
9

10. • 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
10

11. 3) PHARMACOLOGICAL TREATMENT
CONGESTIVE OF HEART FAILURE :
Drug Classes
Used To Treat
CHF :
Cardiac
Glycosides
β blockers
(ACE Inhibitors)
and AT1 Receptor
Antagonists
Diuretics
Vasodilators
Aldosterone
Antagonists
11

12. 3.1] The Cardiac Glycosides (Cardenolides):
•
Drug Members :
i.
Digitoxin (Crystodigin)
ii. Digoxin (Lanoxin)
iii. Deslanoside (Cedilanid-D)
•
Mechanisms of Action :
http://cvpharmacology.com
12

13. • 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.
13

14. 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
14

15. 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
15

16. 3.4] Diuretics :
Classes High Ceiling
of
Loop Diuretics
Diuretics
Furosemide (Lasix) 20,40 & 80 mg
Ethacrynic Acid (Edecrin)
Bumetanide (Bumex)
Benzothiadiazide
Diuretics
Hydrochlorothiazide (Hydrodiuril)
Potassium
Sparing Diuretics
Triamterene (Dyrenium)
Osmotic
Diuretics
Mannitol (Osmitrol)
Clorthalidone (Hygroton)
Chlorothiazide (Diuril)10-20mg/kg
Amiloride (Midamor)
spironolactone (Aldactone)100-200mg
16

17. http://pharmacologycorner.com
17

18. • 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
18

19. 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
19

20. • 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
20

21. •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.
21

22. 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
22

23. 5)
Advances in
treatment of
CHF
Stem cell
therapy
Gene therapy
23

24. 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.
24

25. CLASSIFICATION
1
Adult stem cells
2
Embryionic stem cells
3
Endometrial 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.
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.
It involves extraction of a small amount of
menstrual blood from young healthy donors
that is called as endometrial stem cells.
25

26. Fig: pictorial representation of injecting stem cells in cardiac tissue
http:/www.trialx.com
26

27. • 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,
27

28. • PROCEDURE OF STEM CELL THERAPY
1.
COLLECTION
2. PROCESSING AND
CRYOPRESRVATION
3. INFUSION
4. ENGRAFMENT
AND RECOVERY
28

29. 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 .
29

30. http:/www.wikipedia.org
30

31. • 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 .
31

32. • 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 ca 2+ 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.
32

33. b) ADENYLYL
CYCLASE 6
protein kinase a
phosphorylates
phospholamban
and SERCA2A
activity is
enhanced.
FIG: ROLE OF ADENYLYL CYCLASE (AC6) IN HEART
CONTRACTION
http:/www.sciencedirect.com
Symptoms of
heart failure is
alleviated by viral
delivery of AC6
transgene as result
of SERCA2a
function.
33

34. 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.
34

35. 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.
35

36. FIG : GENE THERAPY PROCEDURE
http://www.trip2medi.com
36

37. • GENE DELIVERY METHODS ;
A) Transvascular
intracoronary antegrade and retrograde delivery :
B) Direct intramyocardial delivery :
http://www.sciencedirect.com
37

38. 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.
38

39. 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
39

40. 2. Biventricular
(cardiac resynchronisation therapy) :
40

41. 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
41

42. • 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.
42

43. 7)
Conclusion
Heart failure is a major health issue with a high rate of
morbidity and mortality
Thus, there is a substantial need for new strategies to
prevent the progression of heart failure.
Until now, heart
failure was seen as an incurable disease.
However, gene
therapy approach have offered the promise of an effective
therapy for reversing systolic heart failure
Great advances in understanding the pathobiology
of HF and their application to further improvements of patient care are withun reach
43

44. Time will tell whether a single target
approach is sufficient to restore heart function and prevent
deterioration or whether multiple gene targets are needed
along with stem cell therapy to eventually replace the
injured myocardium.
Using a viral-delivery gene therapy
approach to treat heart failure by enhancing contractility is
not yet a reality, but substantial progress in that direction
has been made in the last few years.
Great advances in understanding the pathobiology
of HF and their application to further improvements of patient care are
within reach
44

45. •
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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