NEWER TARGETS FOR MYOCARDIAL INFARCTION AND ANGINA PECTORIS

The major cardiovascular conditions -

1. Atherosclerosis
2. Heart failure (CHF, MI, Angina, etc.)
3. Stroke
4. Hypertension
5. Atrial fibrillation
6. Sudden cardiac death
7. Obesity and aging
8. Psychosocial factors
9. Regular alcohol consumption
Most of these conditions are comorbid.

Risk factors -

• Cigarette smoking
• Hypertension (blood pressure 140/90 mm Hg or an antihypertensive medication)
• Low HDL cholesterol (< 40 mg/dl)
• Family history of premature CHD (CHD in male first-degree relative < 55 years; CHD in
female first-degree relative < 65 years)
• Age (men 45 years; women 55 years)
• HDL cholesterol 60 mg/dl counts as a negative risk factor; its presence removes one risk
factor from the total count.

Currently available treatments -

1. Invasive techniques –

• PCI (Percutaneous Coronary Intervention)
• CABG (Coronary Artery Bypass Grafting)

2. Non invasive techniques / Pharmacological treatment –

Drugs - Targets

1. Aspirin - Platelets
2. Glycoprotein IIa/IIIb antagonists - Platelets
3. Clopidogrel- Platelets
4. Nitrates ic and/or iv - Vasospasm
5. Heparin - Thrombin
6. Beta-adrenergic blockers - Sympathetic receptor
7. ACE inhibitor - Endothelial excitability/Ventricular remodeling
8. Statins - LDL, Cholesterol synthesis
9. CCBs - Ca+2 Channels in myocardium

3. Non – pharmacological interventions -

• Diet
• Exercise (but not in CHF, MI or Angina cases)

NEWER, NON-TRADITIONAL ANTI-ISCHEMIC (ANTI – ANGINAL / MI)

AGENTS/TARGETS:

1. Nicorandil:
Structurally a nicotinamide derivative with a nitrate moiety and a dual mechanism of
action. First, it increases potassium ion conductance by opening adenosine triphosphate
(ATP)-sensitive potassium channels, in turn activating the enzyme guanylate cyclase.
Second, it shares the smooth muscle relaxing property of nitrates to vasodilate, lowering
preload through venodilation. The drug also reduces afterload and promotes expression of
endothelial NO synthase.
2. Ivabradine: (phase II)
Specific bradycardic agent and the only one in use and under current clinical
investigation. Selectively inhibit the inward sodium – potassium “If current,” an
important pecemaking current in SA node cells, to slow the rate of diastolic
depolarization and lower heart rate.
3. Trimetazidine:
“3-ketoacyl coenzyme A thiolase (3-KAT) inhibitor,” is a metabolic modulator that
improves myocardial energetic at several levels, partially inhibiting -oxidation of fats by
decreasing activity of mitochondrial enzyme 3-KAT. The drug raises myocardial glucose
utilization, prevents a decrease in ATP and phosphocreatine levels in response to hypoxia
or ischemia, preserves ionic pump function, minimizes free radical production, and
protects against intracellular calcium overload and acidosis.
4. Rho Kinase or “ROCK” inhibitor:
Is an important intracellular enzyme which phosphorylates proteins to affect a number of
cellular functions, among them phosphorylation of myosin, resulting in smooth muscle
contraction and vasoconstriction.
E.g. Fasudil (phase II) has been used to prevent vasospasm, especially in the pulmonary
and cerebral arterial beds, in addition to inhibiting production of VEGF.
5. Ranolazine:
Piperazine derivative that inhibits the late sodium channels, not only lowering total
inward sodium flux but also the subsequent intracellular calcium overload.
6. Spinal Cord Stimulation (SCS):
Invasive and multimechanistic (for refractory angina). SCS raises release of the inhibitory
neurotransmitter -amino butyric acid, lowering the amount of two excitatory aminoacids, glutamate and aspartate, which in turn suppresses processing of the nociceptive A
and C nerve fibers. In addition, SCS also raises -endorphin release, lowering pain
perception.
7. Nebivolol:
A novel Beta1-blocker with a greater degree of selectivity for 1- adrenergic receptors than
other agents in its class and a NO potentiating, vasodilator affect that is unique among
beta-blockers.
8. Inhibition of Caspase 1:
IL-18 is a pro-inflammatory cytokine structurally and functionally related to IL-1 . Both
are initially synthesized as inactive precursors requiring the IL-1 converting enzyme
(ICE or Caspase 1) for cleavage to mature biologically active molecules. Cardiomyocytes
also lose contractile force because of the action of these endogenous cytokines (TNF ,
IL-1Beta).
E.g. Ac-Try-Val-Ala-Asp-Chloromethylketone (YVAD)
9. Granulocyte Colony Stimulating Factor (G-CSF):
Several mechanisms are responsible for this myocardial regeneration: G-CSF increases
circulation of stem cells from bone marrow which can travel to the damaged
myocardium. After myocardial homing, progenitor cells can differentiate into endothelial
cells leading to improved neovascularisation and they secrete several cytokines that are
able to recruit pre-apoptotic myocardium and can stimulate resident cardiac stem cells.
Further, G-CSF has direct effects on cardiomyocytes via the Jak-Stat pathway and can
contribute to myocardial regeneration.
10. Eptifibatide:
Glcoprotein IIb/IIIa receptor inhibitor present on platelets.
11. Non-viral delivery of genetic medicine for therapeutic angiogenesis:
Delivery methods- Target genes
a. Naked plasmid VEGF, eNOs, HGF, Netrins-1,4
b. Scaffolds (Hydrogels, nanoparticles) VEGF, PDGF
c. Cationic polymers or lipids VEGF

d. Genetically engineered stem or progenitor cells SDF 1Beta, VEGF, IGF
e. Plasmid VEGF165, VEGF-2 Intramyocardial injection
f. Plasmid / liposome VEGF165 Intracoronary infusion
12. Nanomedicines:
E.g. (For diagnosis) - Quantum dots (Fluorescence tomography), Gold or I based
nanoparticles (CT), Iron oxide nanoparticles (MRI)
E.g. (For treatment) - Neutral or Cationic liposome (targeted delivery of VEGF, PDGF or
certain genes), Polymeric PLA or PLGA (inhibition of re-stenosis in rats).
13. Cardiovascular Biomarkers:
Three biomarkers that are currently approved by the U.S. FDA for use in cardiovascular
disease management and risk assessment:
• C-Reactive Protein (CRP)
• Lipoprotein-Associated Phospholipase A2 (LP-PLA2)
• Myeloperoxidase (MPO)
Other new biomarkers have also been shown recently to help in CVD prediction and
management:
• Cardiac Troponin T (cTnT)
• Brain Natriuretic Peptide (BNP)
14. Polypill:
Containing more than one drug for enhanced patient acceptability since management of
MI and Angina requires more than one medication.
15. Implantable Automatic Intracardiac Defibrillator (AID)

REFERENCES:

Myron L. Weisfeldt and Susan J. Zieman, Advances In The Prevention And TreatmentOf Cardiovascular Disease, Health Affairs, 26, no.1 (2007) 25-37, doi:10.1377/hlthaff.26.1.25
Bone marrow and circulating stem/progenitor cells for regenerative cardiovasculartherapy, Mohamad Amer Alaiti, Masakazu Ishikawa, And Marco A. Costa, Cleveland,Ohio and Hiroshima, Japan
Developing and assessing cardiovascular biomarkers Razvan T. Dadu, Vijay Nambi, And Christie M. Ballantyne, Houston, Texas
Current Therapeutic Protocol for Unstable Angina and Non-ST-Elevated Myocardial Infarction, Indranill Basu Ray, Division of Interventional Cardiology, Department Of Cardiology, Vijaya Heart Foundation, Chennai.
Randomized Comparison of Eptifibatide Versus Abciximab in Primary PercutaneousCoronary Intervention in Patients With Acute ST-Segment Elevation Myocardial Infarction, Journal of the American College of Cardiology, Published by Elsevier Inc. Vol. 56, No. 6, 2010 doi:10.1016/j.jacc.2009.08.093
G-CSF in patients suffering from late revascularised ST elevation myocardial infarction: Final 1-year-results of the G-CSF-STEMI Trial, International Journal of Cardiology 144 (2010) 399–404
Inhibition of Caspase 1 reduces human myocardial ischemic dysfunction via inhibition o IL-18 and IL-1 , Benjamin J. Pomerantz, Leonid L. Reznikov, Alden H. Harken and Charles A. Dinarello, Departments of Surgery and Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, Contributed by Charles A. Dinarello,December 22, 2000
Nebivolol: a novel beta-blocker with nitric oxide-induced vasodilatation, Robert Weiss, Androscoggin Cardiology Associates, Auburn, ME, USA
Nonviral delivery of genetic medicine for therapeutic angiogenesis, Hyun-Ji Park, Fan Yang, Seung-Woo Cho, Department of Biotechnology, Yonsei University, Seoul 120- 749, Republic of Korea and Department of Orthopaedic Surgery and Bioengineering, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA, Advanced Drug Delivery Reviews, ADR-12188; No of Pages 13
Recent advances in the management of chronic stable angina II. anti-ischemic therapy, options for refractory angina, risk factor reduction, and revascularization, Richard Kones, The Cardiometabolic Research Institute, Houston, Texas, USA, Vascular Health and Risk Management, Dove press journal, 11 Aug 2010.

- By Kumar Amit