Recent advances in Congestive Cardiac Failure

BITS Pilani
Pilani Campus

BITS Pilani
Pilani Campus

Nalla Sri Raviteja Prateek S. Kanade Savani Hiren Sugandha Saboo

Outline
Introduction Epidemiology What is CCF - Pathophysiology Symptoms Recent advances in CCF Newer drugs used in CCF Conclusion References
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Introduction
In simple terms, CHF/CCF is a condition where in the heart is unable to pump sufficient blood to meet the needs of the body. Chronic CHF may be defined as the clinical condition in which an individual expels less than 40% of the blood from the left ventricle per heartbeat (ejection fraction [EF] 40%).A normal individual expels about 55 to 65% of the blood from the left ventricle per heartbeat (EF 5565%).

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Epidemiology
5 Million Americans have Heart failure 500,000 new cases per year 25-50 billion USD per year spent on treating CHF More than 300,000 deaths per year Women relatively run a lower risk of CHF than men

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Causes of CHF
Aging Hypertension Chronic alcoholism History of Myocardial infarction Diabetes Myocarditis Cardiomyopathy Coronary artery disease

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Types of CHF
Right sided heart failure: A improper pumping action of the right ventricle which leads to swelling in the legs and abdomen Left sided heart failure: The failure of the left ventricular pumping leading to congestion in the lungs

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BITS Pilani, Pilani Campus

Pathophysiology

BITS Pilani, Pilani Campus

BITS Pilani, Pilani Campus

Cardiac Re-modelling in CHF

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BITS Pilani, Pilani Campus

Advances in CHF Treatment

Therapeutic Perspectives of Angiotensin-(1-7) in the Treatment of Cardiovascular Disease

BITS Pilani, Pilani Campus

BITS Pilani, Pilani Campus

Ang-(1-7) also exerts antiproliferative actions that could be of interest in several cardiovascular diseases including heart failure and atherosclerosis. The potential therapeutic benefit of Ang-(1-7) is also supported by the fact that endogenous Ang-(1-7) levels or the effect of the heptapeptide are modified in pathological conditions. Ang-(1-7) also seems to play a protective role during acute myocardial infarction, considering that chronic infusion of the heptapeptide reduces arrhythmias [48] and attenuates development of heart failure after myocardial infarction in rats
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Res-erection of Viagra as a heart drug:

Sildenafil

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Reference:

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PDE-5 Inhibitor

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Vasopeptidase Inhibitor
Dual acting compounds that augment the activity of natriuretic peptides while inhibiting RAAS activity may offer benefits for the treatment of cardiovascular disease Eg. Gemopatrilat Samipatrilat Fasidotril Mixanpril Z-13752 A MDL-100240

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Dual NEP/ ACE Inhibitor

NEP Vasopeptidase Inhibitor ACE

ANP & related peptides

Angiotensin II

Vasodilation Sodium excretion Antihypertrophic effect

Blood pressure Cardiac performance Target organ effects

Vasoconstriction Sodium retention Hypertrophic effect

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Statins
- Reactive Oxygen Species (ROS) contribute to the development of heart failure. - Potential source of myocaridial ROS is the NADPH oxidase, which is regulated by the small GTP- binding protein Rac 1. - Statins are useful in reducing the Rac1- GTPase activity. - Eg. Atorvastatin Pravastatin

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Statins: MOA

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Matrix metalloprotease Inhibitor (MMPI)

Matrix metalloproteinases (MMPs) are zincdependent endopeptidases. - MMPs are considered to be key enzymes involved in angiogenesis, since degradation of basement membrane and stromal tissue is an essential process for migration of endothelial cells needed to form new blood vessels. - MMPs play a significant role in extracellular remodeling, and recent studies have demonstrated increased MMP expression and activity with CHF. - Eg. Biphenyl hydroxamate compounds Succinic acid amides

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BITS Pilani, Pilani Campus

Vasopeptidase inhibitors L-arginine and L-carnitine ACE-1 inhibitors Endothelin 1 receptor Cardiac resynchronization therapy in heart failure

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Vasopeptidase inhibitors
Vasopeptidase inhibitors represent a new class of cardiovascular drugs. They function as a combined angiotensin-converting enzyme (ACE) inhibitor and neutral endopeptidase (NEP) inhibitor, the latter of which potentiates the actions of atrial natriuretic peptide (ANP) by minimizing its degradation in the circulation.

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Vasopeptidase inhibitors have also shown to potentiate bradykinin and adrenomedullin, which additionally contribute to cardiovascular regulation. The most extensively researched and promising agents within the class of VP inhibitors is omapatrilat, a mercaptoacyl derivative of a bicyclic thiazepinone dipeptide. It is a single molecule with equal potency and affinity for ACE and NEP inhibition. Although ACE inhibition tends to more selectively benefit high-renin models of hypertension, vasopeptidase inhibition has been shown to be equally efficacious in low-, normal-, and high-renin models.
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Contrary to NEP inhibition alone, omapatrilat has also demonstrated the ability to significantly reduce blood pressure in spontaneously hypertensive rats, the equivalent of essential hypertension in humans. Studies also suggest that omapatrilat has cardioprotective properties, especially in the setting of congestive heart failure. More specifically, animal models have demonstrated omapatrilat to be more effective than ACE inhibition alone in remodeling the heart and improving its contractile function.

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L-arginine and L-carnitine

IN CHF there is deficiency of endothelial NO synthesis. L-arginine supplementation in patient with CHF is associated with improved endothelial dependent vasodilation, resting hemodynamics, exercise tolerance. The potential therapeutic effect of L-carnitin is due to its being an essential cofactor for the transportation of fatty acyl groups into the mitochondrial matrix, where they are oxidized, resulting in the formation of ATP.

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Ace-1 inhibitors

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Ace-1 inhibitors

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The pril family of drugs

Captopril Enalapril Lisinopril Quinapril Ramipril To develop inhibitors with higher therapeutic efficacy and reduced side effects, recent efforts have been directed towards the discovery of compounds able to simultaneously block more than one zincmetallopeptidases (apart from ACE) involved in blood pressure regulation in humans, such as neprilysin and endothelin converting enzyme (ECE-1)
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Endothelin 1 receptor(ET-1)
In CHF overproduction of ET-1. Which produces vasoconstriction and overload heart and disturb its function. Bosantan is a antagonist of ET-1 receptor and potentially useful in CHF. Recently ,It has been reported that at end stage of CHF ,ET receptor pattern varies of the ETA receptor which would make it interesting to design a drug which act on this receptor.

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Cardiac resynchronization therapy in heart failure(CRT)

Newer non-pharmacological therapy A CRT device sends small, undetectable electrical impulses to both lower chambers of the heart to help them beat together in a more synchronized pattern. This improves the heart's ability to pump blood and oxygen to the body.

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In addition to the heart device, insulated wires called leads are implanted for two purposes: to carry information signals from your heart to the heart device, and to carry electrical impulses to your heart. Cardiac resynchronisation therapy using a pacing device is recommended as a possible treatment for people with heart failure where all of the following circumstances apply. They have moderate to severe symptoms of heart failure that are affecting their daily life, measuring class 3 or class 4 in the New York Heart Association classification system.
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Cell therapy for heart disease

Cell based therapy for heart diseases, ranging from myocardial infarction, hibernating myocardium to ischemic and non ischemic cardiomyopathies, is a potentially transformative approach to address unmet needs for the treatment of chronic diseases. In this context, several investigative teams have undertaken the approach of starting with a reasonable candidate cell, whether that be an adult stem cell, such as a mesenchymal stem cell(MSC) or cardiac stem cell(CSC) or a pluripotent stem cell, and then enhancing that cell by genetic modification or incubation with factors or cytokines capable of optimizing the ability of the cell engraft, survive, and/or differentiate.
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This approach has uniformly produced positive results using MSCs and CSCs with a number of genetic modifications. Overexpression of the serine/ threonine kinase ,glycogen synthase kinase (GSK)-3 beta enhances therapeutic properties of bone marrow derived MSCs in a mouse model of myocardial infarction. GSK-3 beta overexpression enhances MSC survival after 8 weeks, promotes MSC differentiation into cardiac myocytes.

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BITS Pilani, Pilani Campus

BITS Pilani, Pilani Campus

BITS Pilani, Pilani Campus

BITS Pilani, Pilani Campus

Calcium and integrin-binding protein-1(CIBI)

The small EF hand domain-containing protein ca+2 and integrinbinding protein-1(CIBI) in a screen for previously unknown regulators of cardiomyocyte hypertrophy CIBI localizes primarily to the sarcolemma in mouse and human myocardium, where it anchors calcineurin to control its activation in coordination with the L-type ca+2 channel. CIBI protein amounts and membrane association were enhanced in cardiac pathological hypertrophy, but not in physiological hypertrophy. Consistent with these observations, CIBI 1deleted mice showed a marked reduction in mycardial hypertrophy, fibrosis, cardiac dysfunction and calcineurin nuclear factor of activated T cells(NFAT) activity after pressure overload
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BITS Pilani, Pilani Campus

BITS Pilani, Pilani Campus

BITS Pilani, Pilani Campus

2 octynyladenosine(YT-146)
2-octynyladenosine(YT-146) is a novel adenosine receptor(AR) agonist and having a cardio protective action. The study for cardiac receptor subtypes involved in the cardioprotective effects of 2-octynyladenosine (YT-146), a novel adenosine receptor (AR) agonist.

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Thank You for patient listening!

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