Volume Five:

Pharmacological Agents in Treatment of Cardiovascular Diseases

 

https://www.amazon.com/dp/B07MGSFDWR

On Amazon.com since 12/23/2018

Volume Authors, Curators and Co-Editors:

Justin D. Pearlman, MD, PhD, FACC:

Editorials and Clinical Pearls, Author

Larry H. Bernstein, MD, FCAP

and

Aviva Lev-Ari, PhD, RN

“I think this volume offers a pleasant way to broach through a range of thought- provoking topics with original sources made convenient and accessible, augmented by expert voice sorting wheat from chaff and adding context and insight by curation.”

Dr. Justin D. Pearlman, MD, PhD, FACC, August 13, 2018

PREFACE

by Justin D. Pearlman, MD, PhD, FACC

Pharmacologic therapy represents the dominant strategy for management of cardiovascular disease and consequences, deferring, complementing and often supplanting structural and functional interventions. The general strategy of medical management is to identify the biochemicals that control cardiovascular functions and responses, identify the consequences of push and pull (stimulation, potentiation, inhibition, blockade, counteractivity), check benefits and harm, systematically document the impact, both in population studies and in individuals, make wise choices, and optimize dosing.

Medications mimic or modify natural biologic activities. Therefore genomics (the study of gene products, especially, messengers and receptors) and the cascade of signaling pathways that modulate responses  identifies the myriad but theoretically finite possibilities for chemical intervention.

Often there are many pathways that affect or are affected by cardiovascular disease, and multiple ways to promote desirable changes. Elucidation of the biochemical signal changes that correspond to or respond to cardiovascular disease conditions and treatments provides both biomarkers of patient health status and targets for therapy.

The process of homeostasis resists change,  including resisting desirable changes that aim to correct maladaptive biology. Thus medication to block an excess in heartrate and blood pressure, for example, leads to upregulation in the number and sensitivity of blocked receptors as well changes in activity of sibling pathways, which mitigate the impact of the blocking medication and promote rebound worsening of the primary concern if the medication gets interrupted. These issues influence combination therapy choices as well as concern about compliance with prescriptions.

Therefore this guided tour of curated data relating to medical management of cardiovascular diseases draws from the human genome project to identify treatment opportunities, pathophysiology to understand the impact of disease and maladaptive responses, clinical disease and pharmaceutical classifications, and clinical trial results to clarify expected outcomes. Curation also addresses context, insight and opportunity. Review of all of the above by teams of experts leads to formulation of guidelines, but each patient is a unique individual for whom customized optimization offers further benefits. Optimal care requires understanding of all of the above to guide and optimize the offering and patient education for wise choices promoting optimal quality and quantity of life despite the presence of cardiovascular disease.

 

Voice of Aviva Lev-Ari, PhD, RN

The most updated treatment strategy for CVD patients with comorbidity of Diabetes is present in the following report:

Cardiovascular (CV) Disease and Diabetes: New ACC Guidelines for use of two major new classes of diabetes drugs — sodium-glucose cotransporter type 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) for reduction of adverse outcomes

https://pharmaceuticalintelligence.com/2018/11/27/cardiovascular-cv-disease-and-diabetes-new-acc-guidelines-for-use-of-two-major-new-classes-of-diabetes-drugs-sodium-glucose-cotransporter-type-2-sglt2-inhibitors-and-glucagon-like/

List of Contributors

 

• Justin D. Pearlman, MD, PhD, FACC, Content Consultant to Series A: Cardiovascular Diseases 

PREFACE, Introduction to Part One, Summary to Part One, Introduction to Part Two, Summary to Part Two, EPILOGUE

and Clinical Pearls

• Larry H. Bernstein, MD, FCAP, Volume Co-Editor and Author

47 Single-authored articles and 21 Co-curations

1.8, 2.17, 4.18, 9.10, 13.1, 13.2, 13.3, 13.6, 14.1, 14.2, 15.1, 15.2, 15.3, 15.5, 15.6, 15.7, 15.8, 15.9, 16.2, 16.3, 16.8, 17.1.1, 17.3.1, 17.3.4, 17.3.7, 17.3.8, 17.3.9, 17.4.2, 17.4.4, 18.1.1, 18.2.3, 18.2.4, 18.2.5, 18.2.8, 19.1.1, 19.1.2, 19.1.3, 19.1.4, 19.3.3, 20.1.1, 20.1.2, 20.1.3, 20.1.4, 20.2.1, 20.2.2, 20.2.3, 20.3.1

• Aviva Lev-Ari, PhD, RN, Volume Co-Editor and Curator

Single Author Curations (N=65)	Single Author Reporting Articles (N=92)	Co-Curation with one Author (N=17)	Co-Curation with two Authors (N=7)
Classification of Drugs, 1.3, 2.1, 2.2, 2.3, 2.4, 2.6, 2.7, 2.8, 2.12, 2.13, 2.14, 4.1, 4.2, 4.3, 4.6, 4.13, 5.3, 5.4, 5.6.6, 5.9, 6.6, 6.7, 6.8, 6.10, 7.1, 7.10, 8.1, 8.2, 9.1, 9.4, 9.7, 9.8, 10.1, 11.1, 11.2, 11.4, 11.5, 11.6, 11.7, 11.8, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 12.10, 12.11, 12.12, 12.13, 16.1, 17.2.3, 17.6.1, 18.1.3, 18.2.6, 19.1.5, 19.2.1, 19.2.4, 19.2.5, 19.3.1, 20.2.4	1.2, 1.4, 1.5, 1.6, 1.7, 2.5, 2.9, 2.10, 2.11, 2.15, 2.16, 3.1, 3.2, 3.3, 3.4, 4.4, 4.5, 4.7, 4.8, 4.9, 4.11, 4.14, 4.15, 4.16, 5.2, 5.5, 5.6.1, 5.6.2, 5.6.3, 5.6.4, 5.6.5, 5.6.8, 5.6.9, 5.8.1, 5.8.2, 5.11, 5.12, 5.13, 6.1, 6.2, 6.3, 6.4, 6.5, 6.9, 6.11, 6.12, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.11, 8.3, 8.4, 8.5, 9.2, 9.3, 9.5, 9.6, 9.9, 9.11, 9.12, 10.6, 11.3, 13.4, 13.5, 16.4, 16.5, 16.6, 16.7, 17.1.2, 17.1.4, 17.1.5, 17.3.2, 17.3.3, 17.3.5, 17.3.12, 17.4.5, 17.5.1, 17.5.2, 17.5.3, 17.6.2, 18.1.2, 18.2.7, 19.2.2, 19.2.3, 19.3.2, 20.2.5, 20.2.6, 20.3.2	4.17, 5.1, 5.6.7, 5.7, 5.8.3, 7.9, 10.4, 17.2.1, 17.2.2, 17.3.10, 17.4.1, 17.4.3, 17.4.6, 18.2.1, 18.2.2, 19.1.6, 20.2.7,	1.1, 1.9, 4.10, 10.2, 10.3, 10.5, 17.1.3

Productive Collaborations among Team members:

• Curators: Justin D. Pearlman, MD, PhD, FACC, Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

1.1, 10.2, 10.5

• Curators: Larry H. Bernstein, MD FCAP, Justin D. Pearlman, MD, PhD, FACC, and Aviva Lev-Ari, PhD, RN

10.3, 17.1.3, 17.2.1 

• Authors and Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

4.17, 5.6.7, 5.8.3,10.4, 17.2.2, 17.3.10, 17.4.1, 17.4.6, 18.2.1, 18.2.2, 19.1.6, 20.2.7

• Curators: Lal, V., Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

4.10,

• Curators: Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

5.1, 5.7

• Curators: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

7.9, 17.4.3

• Sudipta Saha, PhD, Author and Curator

15.4, 17.3.11, 19.1.7, 19.1.8, 19.1.9, 20.3.3

• Demet Sag, PhD, Author

15.10, 16.9, 20.3.4

• Danut Dragoi, PhD, Author and Curator

4.12

Classification of Cardiac Medications: An Overview of Best of Practice in the US by Action and Use, Common Medications, Contraindications, Drug interactions, Side effects and Adverse effects

Reporter and Curator: Aviva Lev-Ari, PhD, RN

Here is the complete list of the top 10 cardiovascular drugs with data on growth and details on their manufacturers.

The Complete List and Analysis of the Best Selling Cardiovascular Drugs in 2017. All the Top Cardiovascular Products in the Pharmaceutical and Biotechnology Industry with detailed performance and future trends

Cardiovascular remains one of the largest disease areas in the pharmaceutical business together with oncology, rheumatology, respiratory, anti-virals, and others. Total revenues for the 10 best selling cardiovascular medications approached 12 billions USD in 2017.

WATCH VIDEO 

https://www.igeahub.com/2018/05/04/best-selling-drugs-2018/

Sources: SEC filings, companies websites, and annual reports.

SOURCE

Luca Dezzani, MD, Group Global Medical Director at Novartis Oncology, Physician & Author

https://www.linkedin.com/pulse/10-best-selling-drugs-2018-cardiovascular-luca-dezzani-md/

The total revenue from branded cardiovascular drugs in 2017 is projected to be just over $40 billion. Top companies in this space are putting a heavy focus on the anti-thrombotic segment, as these drugs continue to bring in the biggest profit and dominate the cardiovascular market.

Figures ($M) represent projected 2017 global sales of cardiovascular products. Credit: GlobalData.

SOURCE

https://www.pharmaceutical-technology.com/comment/top-players-cardiovascular-disease-2017/

This overview covers the Best of Pharmacological Practice for treatment of cardiac patients in the US.

Following the overview of Classification of Cardiac Medications, the book presents to the eReader two parts:

• Part One of the book covers clinical trials comparing these medications with the new agents developed, approved and are in the monitoring period after becoming available in the market.
• Part Two of the book presents the development of Biomarkers for cardiac disease diagnosis and the roles that these biomarkers play in treatment selection by indication.

Keywords

cardiac output: the amount of blood ejected in liters;/minute by the heart consists of blood Input from:

(1) preload – volume in the left ventricle (LV) just prior to contraction

(2) afterload – resistance to blood being ejected by the left ventricle

(3) contractility of the heart – amount of force and pressure pumping blood out of the ventricles (mechanical pumping action) for a giving combination of preload and afterload (higher contractility will pump harder under the given conditions)

(4) Heart rate

For adults 18 and older, a normal resting heart rate is between 60 and 100 beats per minute (bpm), with some changes expected depending on physical condition and age. For children ages 6 to 15, the normal resting heart rate is between 70 and 100 bpm, according to the AHA.

Chronotropic medications: drug affecting the heart rate (HR)

• Positive chronotropic medications increase HR
• Negative chronotropic medications decrease HR

Dromotropic medications: drugs affecting the speed with which impulses pass through the conduction system

• Positive dromotropic medications increase speed of impulses
• Negative dromotropic medications decrease speed of impulses

Dysrhythmia: abnormalities in the heart beat pattern and mechanism produced by the electric activity of heart

Inotropic medications: drugs affecting force of contraction

• Positive Inotropic medications increase the force of contraction – resulting in increase of cardiac output
• Negative Inotropic medications decrease increase the force of contraction – resulting in decrease of cardiac output

Myocardial irritability: heart muscle malfunction in response to external stimuli: hypoxia, ischemia, abnormal electrolyte levels, particular hormones, medications and physical trauma

Refractory period: The heart “propagates” signal which means it responds to depolarization (ion shifts) with further depolarization, but there is a recovery period in the cardiac cycle when the heart is unable or less able to respond to another depolarization event (electric activity leading to contraction) as it recovers from the prior heartbeat

• Absolute refractory period – time interval after a heartbeat when tissue is unable to respond to another stimulus
• Relative refractory period – time interval after a heartbeat when ability to respond is limited to only to stronger than usual stimuli

Cardiac Medications by Drug Class – An Overview

Class I.    Nitrates and Nitrites

• Action and Use
• Increase the Oxygenated blood flow to the myocardium by dilating the coronary and systemic blood vessels
• Prophylactic treatment to prevent or minimize angina in patients with Coronary Artery Disease (CAD)
• Dilation of systemic vascular bed results in pooling of blood in the peripheral vascular system resulting in reduction of total workload of the LV by reducing preload and afterload, resulting in reduction of myocardial oxygen demand

Common Nitrates and Nitrites:

• Isosorbide Denitrate
• Isosorbide
• Nitroglycerin Sublingual (SL)
• Nitroglycerin SR
• Nitroglycerin Topical
• Nitroglycerin Transdermal 

Side effects: headache (50%), flushing, postural hypotension, rash, local tingling sensation, GI upset with oral use, contact dermatitis with topical use

Transdermal – New systems to delivery medication through the skin can provide steady adequate levels of medications that might otherwise require taking a pill every 5 minutes. However, nitrate impact is subject to “tachyphylaxis” which means continual use can reduce the benefits compared to intermittent shorter acting use as needed.

Introduction to Transdermal Drug Delivery (TDD) system and nanotechnology  |Comments

Tilda Barliya, PhD

Class II.   Beta-Adrenergic Blockers (BB)

Action and Use

·       Reduced pulsatile force (beta blockers)

These work by blocking certain nerve and hormonal signals to the heart and blood vessels, thus lowering blood pressure.

• In therapeutic doses they block beta-adrenergic receptors (Beta1) in cardiac muscle
• In high doses, they may block beta-adrenergic receptors (Beta2) in the lungs causing airway restriction not indicated in Patients with asthma and COPD
• Blocking beta-adrenergic receptors leads to reduction in renin activity, resulting suppression of the renin-angiotensin-aldosterone

Outcomes:

1. Competition for binding of catecholamines at beta-adrenergic receptors site
2. Reduction in systolic and diastolic Blood Pressure (BP)
3. Negative inotropic (force of contraction) and chronotropic (heart rate effect)

• Management of hypertension, angina pectoris, acute myocardial infraction (MI) and supraventricular tachycardia, protection from maladaptive changes from heart failure
• Indicated for patients with suspected MI and unstable angina if not at risk for cardiogenic shock (in first 24 hours of acute coronary syndrome, beta blockers can increase death from cardiogenic shock, avoidable by switching to very short acting esmolol), helpful to prevent ventricular fibrillation, helpful with caution for heart failure.
• Counter potentially toxic effects of excess beta-adrenergic stimulation from pheochromocytoma, hyperthyroidism, or high stress (broken heart syndrome, takotsubo cardiomyopathy).

Outcomes:

1. Reduction in HR, myocardial irritability and force of contraction
2. Depression of automaticity – allowing the heart to initiate impulses on its own [without a defibrillator of CPR stimulating the Sinus Node (SinoAtrial (SA) node)
3. Reduction in AtrioVentricular (AV) Node and intraventricular dromotropic (conduction velocity) effects of Right Ventricle and Left Ventricle
4. In some patients it controls panic attack and stage appearance performance anxiety

Common Beta-Adrenergic Blocker Medications:

• Atenolol (Tenormin)– side effects: Bradycardia, Hypotension, worsening CHF, worsening PVD, Bronchospasm, some evidence of increased risks of cancer/reduced lifespan
• Sotalol – side effects: Impotence, GI upset, Increased triglyderides
• Metoprolol (Lopressor, Toprol XL)– side effects: decrease HDL, mask signs of Hypoglycemia
• Nadolol (Corgard)
• Propranolol (Inderal)
• Timolol
• Acebutolol (Sectral)
• Betaxolol (Kerlone)
• Pindolol (Visken)
• carvedilol (Coreg)
• penbutolol (Levatol).
• Bystolic (Metabolized nebivolol) increases vascular NO production, involves endothelial ß2-adrenergic receptor ligation, with a subsequent rise in endothelial free [Ca2+]i and endothelial NO synthase–dependent NO production

Contraindications:

• Greater than 1^st-degree heart block (0.20 second)
• Risk of cardiogenic shock
• RV failure secondary to pulmonary hypertension
• Sinus bradycardia
• Cardiogenic shock
• Aortic or Mitral valve disease
• Hyperactive airway syndrome (asthma or bronchospasm)
• Severe seasonal allergies (allergic rhinitis)
• Psychotropic drugs that use an adrenergic augmentation
• Patients with diagnosis of DM, myasthenia gravis, hepatic or renal impairment

Other drug classes developed to lower blood pressure with different mechanism of action,

i.e., captopril, the first orally-active ACE inhibitor, in 1975. Captopril was approved by the United States Food and Drug Administration in 1981, used as Antihypertensive drug.

The orally active, potent and selective nonpeptide AT₁ receptor blocker losartan was developed. In 1995 losartan was approved for clinical use in the United States and since then six additional ARBs have been approved.

Antihypertensive drugs are covered, below in the Renal System Medical section. See, below, Class VIII, C-3 and C-4 for ACEI and ARBs:

• Angiotensin converting enzyme (ACE) inhibitors
• AngiotensinII Receptor Blockers

Class III. Calcium Channel Blockers (CCB) 

Action and Use

Class	Description
Hyperpolarization mediated (Calcium channel blocker)	Changes in the resting membrane potential of the cell affects the level of intracellular calcium through modulation of voltage sensitive calcium channels in the plasma membrane.
cAMP mediated	Adrenergic stimulation results in elevated levels of cAMP and protein kinase A, which results in increasing calcium removal from the cytoplasm.
cGMP mediated (Nitrovasodilator)	Through stimulation of protein kinase G. Until 2002, the enzyme for this conversion was discovered to be mitochondrial aldehyde dehydrogenase. Proc. Natl. Acad. Sci. USA 102 (34): 12159-12164.doi:10.1073/pnas.0503723102http://www.pnas.org/content/102/34/12159.long

Class	Example
Hyperpolarization mediated (Calcium channel blocker)	adenosine amlodipine (Norvasc),diltiazem (Cardizem,Dilacor XR) andnifedipine (Adalat, Procardia).
cAMP mediated	prostacyclin
cGMP mediated (Nitrovasodilator)	nitric oxide

• Non-nitrate hypotensive agents that reduce BP by direct effects on vascular smoo

• Are Class IV antiarrhythmic drugs that inhibit calcium ion influx through slow channels into cells of myocardial and arterial smooth muscle, cardiac and peripheral blood vessels
• Intracellular calcium remains below levels needed to stimulate cell
• Dilate coronary arteries and arteriole ans prevent coronary artery spasm
• Myocardial Oxygen delivery is increased, preventing angina
• Slow conduction through the SA abs AV nodes, resulting in a lower HR and negative inotropic effect (decrease contraction force)
• Decreased automaticity and conductivity (of force and pressure to pump blood out of the ventricles) by blocking the flow of calcium into the cell
• Decreased systemic vascular resistance (SVR) and decreasing afterload by dilating peripheral arteriols
• Reduce arterial BP (antihypertensive effect) ad reducing heart rate
• CCB are used for Angina

1. Vasospastic angina – Prinzmetal’s variant, aka angina at rest
2. Chronic stable – Classic and activity-induced angina
3. Essential hypertension
4. For treatment of atrial fibrillation, atrial flutter and supraventricular tachycardia

Common Calcium Channel Blocker Medications:

• Amlodipine (Norvasc)
• Diltiazem (Cardizem, Dilacor Regular Release (RR) and Extended Release (XR), Tiazac)
• Nifedipine (Adalat, Procardia) RR and SR
• Verapamil (Calan, Covera HS, Verelan, Isoptin) RR and SR

Side effects: Hypotension, Peripheral edema, Tachycardia, Flushing, Headache, GI upset

Contraindications:

• known hypersensitivity to the CCB,
• sick sinus syndrome (unless pacemaker is in place),
• Severe hypotension BP less than 90/60
• 2^nd degree of heart block

1. Type I: Wenchebach – progressive PR prolongation until a QRS is dropped
2. Type II: P waves are constant until a QRS is dropped

• 3^rd degree of heart block – no association between P waves and QRS, ventricular HR is between 20 to 40bpm

Drug interactions: BB and digoxin – may have an additive effect on prolongation of the AV node conduction, may increase digoxin or quinidine levels leading to toxicity

Class IV. Peripheral Vasodilators 

This class will be covers again, below in the context of Renal Medication: Antihypertensive Agents, See Class VIII, below

Action and Use

·       Reduced volume (diuretics)

Diuretics enhance renal excretion of sodium. Sodium is the major determinant of circulating volume. Too much blood volume for the amount of vascular space elevates blood pressure. Clinical trials show that use of diuretics to lower blood pressure can prevent strokes, non-inferior to vasodilators and recommended as first line agents.

·       Increased vascular space (vasodilation)

Alternatively, the pressure can be lowered by increasing the vascular space for a given vascular volume. Examples of mediators for arterial tone (degree of dilation) include

1. nitric oxide
2. prostacyclin and
3. endothelin

• Non-nitrate hypotensive agents that reduce BP by direct effects on vascular smooth muscles of arteries (sodium nitroprusside work equally in all vessel beds)
• Act directly on vascular smooth muscle to induce peripheral vasodilation, resulting in lowered arterial BP, increased HR and increased cardiac output (CO)
• Used to treat Hypertension (HTN) and as an adjunct in treating CHF
• Vasodilators are used to treat peripheral vascular disease (PVD) by increase of blood flow to extremities

Common Peripheral Vasodilator Medications:

• Hydralazine HCL
• Nitroprusside
• Prazosin (Zosin) 

Side effects: Dizziness, Hypotension, Headache, Palpitations, tachycardia, Peripheral edema, Orthostatic hypotension, “first dose syncope” with Prazosin

 

Class V.   Cardiac Glycosides – Action and Use

Primarily used in CHF

Used to treat atrial dysrhythmias

Increase contractility and efficiency of myocardial contraction

Produce positive inotropic action,

• Increase in force of myocardial contraction
• Decrease the conduction velocity through the AV node 

Common Cardiac Glycoside Medications:

• Digoxin
• Digitoxin 
• Midodrine
• Milrinone

Side effects: Headache, Nausea & Vomiting, Loss of appetite, Anorexia, Visual disturbances (yellow vision or halo effect), Rash, Cardiac dysrhythmias. Multiple studies reported increased mortality from digoxin, favoring limited short term use in patients with rate control issues and low blood pressure limiting alternative rate control methods.

Mortality associated with digoxin was highest when the potassium level was low. The mortality risk with a high digoxin level (digoxin 2.2 versus 0.6 ng/mL) was much greater when the pre-dialysis K level was low (HR 2.53 with K < 4.3 mEq/L) than when the K was high (HR 0.86 with K > 4.6 mEq/L).

Serum digoxin concentration was associated with a 19% higher adjusted hazard of death for each 0.5-ng/ml increase (p = 0.0010); these results were similar for patients with and without heart failure. Compared with propensity score–matched control participants, the risk of death (adjusted HR: 1.78; 95% CI: 1.37 to 2.31) and sudden death (adjusted HR: 2.14; 95% CI: 1.11 to 4.12) was significantly higher in new digoxin users.

Contraindications: Known hypersensitivity to digitalis, no full loading doze if digoxin given previous week, presence of digoxin toxicity, conditions of: renal insufficiency, Hypokalemia, acute MI, Heart block, Cor pulmonale, Hypothyroidism, lung disease

Drug Interactions: Diuretics, corticosteroids, amphotericin B, laxatives and sodium polystyrene sulfonate may cause hypokalemia and increase the risk of digitalis toxicity. Quinidine, verapamil and amiodarone increase digoxin levels, digoxin dose needs be decreased by 50%. Erythromycin and nefazadone may increase digoxin levels.

Class VI Antidysrhythmics – Class I-A, I-B, I-C and

• Class II, above

• Class III, above

• Class IV, above

Class I-A – Fast sodium channel blockers: Action and Use

• Used to treat both arterial and ventricular dysrhythmias: prevent recurrence of premature ventricular contractions and ventricular tachycardia that are not severe enough to require cardioversion
• Prolongs the refractory period (able to respond only to a strong stimuli) by depressing myocardial contractility and excitability
• Reduce the rate of spontaneous diastolic deporalization in pacemaker cells, resulting in suppression of ectopic focal activity
• Disopyramide shortens sinus node (SA) recovery time and increases atrial and ventricular effective refractory period
• Quinidine is a chemical cardioversion agent useful to convert atrial fibrillation to normal sinus rhythm

Common Antidysrhythmics Medications: Class I-A – Fast sodium channel blockers –

• Disopyramide
• Moricizine
• Procainamide
• Quinidine-RR
• Quinidine-SR

Side effects: Mild hypotension, Blurred vision, Dry mouth, Urinary hesitancy, Constipation, GI upset, Diarrhea, Drug fever, Rash, Photosensitivity, Pruritis

Contraindications: Cardiogenic shock, 2^nd and 3^rd degree of heart block, Severe heart failure, Hypotension

Caution in use of Disopyramide in the presence of Bundle branch block, Myocarditis, other cardiomyopathy, Myasthenia gravis, Angle closure (narrow angle) glaucoma

Drug interactions:

1. Anticholinergic drug compound, other Anticholinergic: TCA, Antihistamines,
2. Disopyramide may increase warfarin-induced hypoprothrombinemia,
3. Phenytoin and Rifampin may increase metabolism of disopyramide and decrease blood level

Class I-B – Action and Use

• Decrease the refractory period
• Suppress automaticity in the Bundle of His-Purkinje system
• Elevate the electrical stimulation threshold of ventricle during diastole
• Treats or prevents ventricular dysrhythmias 

Common Antidysrhythmics Medications: Class I-B 

• Lidocaine
• Mexiletine
• Tocainide

Side effects: Dizziness, Vertigo, Lightheadedness, Hypotension, Nausea, Drowsiness, Worsening CHF, Confusion, Dyspnea, Heart block, Tinnitus, Tremors

Contraindications: hypersensitivity to amide-type anesthetics, Stokes-Adams syndrome, unrelated sinus bradycardia, Severe degree of SA, AV and intraventricular heart block, hypokalemia needs be corrected before treatment with antidysrhythmics

Drug interactions: Barbiturates descrease Lidocaine activity, Effect of Lidocaine is increased by BB, quinidine, phenytoin and procainamide. Incompatibility with Lidocain infusion: Phenytoin and cefazolin 

Class I-C – Action and Use

• Decrease automaticity and conductivity through the AV node and ventricles,
• Used to treat life-threatening ventricular dysrhythmias 

Common Antidysrhythmics Medications: Class I-C

• Flecainide
• Propafenone

Side effects: Dizziness, Blurred vision, nausea, headache, Lightheadedness, Dyspnea Palpitation, Fatigue, Chest pain, Tremors

Contraindications: Hypersensitivity to Flecainide, severe degrees of heart block, Intraventricular blocks, cardiogenic shock, hepatic failure

Drug interactions: Cimetidine may increase Flecainide levels, Flecainide may increase Digoxin level by 25%, Beta-blockers enhance negative inotropic effects (decrease contractility)

Antidysrhythmics – Class II – Beta blockers, see above

Antidysrhythmics – Class III – Potasium Channel Blockers 

Action and Use

• Prolongs repolarization and refractory period
• Decreases intra-ventricular conduction
• Used to treat ventricular tachycardia and ventricular fibrillation
• Used to treat supraventricular tachycardias

Common Antidysrhythmics Medications: Class III 

• Amiodarone (Cordarone, Pacerone)

Side effects: Skin and corneal pigmentation (lipofuscinosis), nausea, mild anorexia, muscle weakness, hypotension, constipation

Contraindications:

• Hypersensitivity to amiodarone
• Cardiogenic shock
• Severe sinus bradycardia
• Severe degrees of heart block – 3^rd level
• Hepatic disease

Use cautiously in: Hashimoto’s thyroiditis, goitter, hyper or hypo-thyroidism, CHF, electrolyte imbalance, preexisting pulmonary disease, cardiac surgery, sensitivity to iodine

Drug interactions:

1. Amiodarone increases Digoxin levels, Disopyramide, Flecainide, Procainamide, Quinidine, Lidocaine, Cyclosporine (immunosuppressant)
2. Amiodarone increases effects of anticoagulants
3. Bradycardia effects are greater when used with verapamil, Diltiazem and BB
4. Amiodarone increases phenytoin blood levels 2 – 3 fold
5. Amiodarone level is been increases by Cimetidine and Ritonavir

Antidysrhythmics – Class IV – Calcium Channel Blockers, see above

 

Class VII. Blood Modifying Agents:

A. Anticoagulants

B. Antiplatelets

C. Thrombolytics and

D. Medications to Lower Cholesterol

 

A. Anticoagulants

A-1.    Anticoagulants – Oral medications 

Action and Use

Prevent or delay coagulation, treat and prevent thromboembolic disorders at Patients at risk for one or more:

• Deep vein thrombosis (DVT)
• Pulmonary embolism (PE)
• Acute myocardial infaction (MI)
• Heart valve replacement (bioprosthetic and mechanical)
• Atrial Fibrilation (a-Fib)
• Antiphospholipid syndrome (a) phosphatides (cell membrane) (b) sphingomyelins (brain, tissue of nervous system)

Vitamin K plays a role in the extrinsic pathway (fibrin formation within seconds) is been measured by PT and INR and in the intrinsic pathway in the clotting cascade in which fibrin formation occurs and takes several minutes and is measured by APTT (i.e., Heparin)

Warfarin (Coumadin and its derivatives) prevents conversion of vitamin K, thereby decreasing its production in the liver, resulting in reduction of clotting factors: II, VII, IX, and X – affecting the clotting cascade. Coumadin is bound to albumin, it is metabolized in the liver.

Common Anticoagulant Oral Medications:

• Coumarin derivative warfarin sodium (Coumadin) is probably the most frequently used in the US for the management of anticoagulation. Warfarin (Coumadin) has a narrow therapeutic range INR 2 to 3, usual dose 1 to 15 mg daily, (3.0 to 4.5 range if the Patient has a valve replacement.)
• Bishydroxycoumarin (Dicumarol) – a Coumarin derivative, given orally 200-300 mg on day 1, then 25 to 200 mg daily based on PT (1.5 to 2.5 times the control value.)

Contraindications:

• Avoid Coumadin to Pregnant patients, Bishydroxycoumarin (Dicumarol) can be given to lactating patients.
• Allergy to Coumarin, hemorrhaging tendencies, malignant hypertension
• Patients with co-morbidities: i.e., liver failure, CHF, problems with metabolism of Coumadin
• Complex Drug interactions:

Drugs that potentiate Action: Tylenol, Aspirin, Antibiotics, H2 histamin antagonists, Loop Diuretics, NSAIDS, Sulfonamides, Vitamin E

Drugs that decrease Action: Alcohol, Barbiturates, oral contraceptives, Spironolactone, Thiazide drugs, Vitamin K (phytonadione)

If there is significant bleeding, physician may order transfusion of fresh frozen plasma (FFP) or prothrombin concentrate.

 

A-2.    Anticoagulants – Injectable medications (Subcutaneous (SC) or Intravenous (IV)

Heparin (a heterogeneous group of carbohydrates) and related medications

Action and Use

• Plays active role in the intrinsic pathway – formation of fibrin in several minutes in the clotting cascade
• Heparin combines with plasma heparin cofactor named antithrombin III (ATIII).
• This complex causes inactivation of specific clotting factors (IIa, Xa, XIIa, Xia, and IXa) in the clotting cascade.
• This complex inhibits conversion of fibrinogen to fibrin, prevents formation of a fibrin clot, and inhibits thrombin.
• Heprin Molecule: molecular weight: 3,000 to 30,000 daltons (d). Average is 15,000
• Standard measure used is in unfractionated heprin (UFH), i.e., 15,000 d.
• Low molecular weight heparin (LMWN) – range of molecular weight: 4,000 to 6,500 d.

Because of Heparin’s immediate effect – it is the choice of treatment for Patients with cardiovascular and vascular events: DVT, PE, embolism as a result of atrial fibrillation

It is used prophylactically for Patients at risk for developing thrombi as a result of surgical intervention

In weak concentration it is used to flush vascular access devices for maintaining access and prevention of thrombus formation 

Common Anticoagulant injectable Medications:

• Heparin (Liquaemin) IV, SC
• Ardeparin (Normiflo) PO, IM, IV, SC
• Dalteparin (Fragmin) PO
• Danaparoid (Orgaran) PO
• Enoxaprin (Lovenox) SC (therapeutic: 1mg/kg) – APTT labs ordered Q 6 hours until 2 consecutive therapeutic levels are obtained. At that time, APTT can be ordered q 24 hours.
• Tinazaparin (Innohep) SC

Contraindications:

• Uncontrolled bleeding, known hypersensitivity and thrombocytopenia
• Should no be given with ASA and NSAIDS
• LMWH are contraindicated in patients with active bleeding, thrombocytopenia and Heparin allergy and allergy to pork products.

Complex Drug interactions:

Aspirin, NSAIDS and antiplatelet agents – can potentiate the anticoagulation effect and increase the bleeding

Side effects: Hemorrhage, hematuria, epistaxis, bleeding gums, thrombocytopenia

Adverse effects:

HITT – a serious form of thrombocytopenia (<100,000/mm cubic) called heparin-induced platelet aggregation – white clot syndrome: begins between 3 and 12 days following initiation of heparin therapy. HITT can be fatal if not treated aggressively.

Longer than 6 month of heparin therapy may cause osteoporosis

 

Other Anticoagulant Medications developed recently, see numerous articles in the book, i.e., 4.6       Advantages and Disadvantages of Novel Oral Anticoagulants (NOACs)

https://pharmaceuticalintelligence.com/2018/03/20/advantages-and- disadvantages-of-novel-oral-anticoagulants-noacs/

ELIQUIS (apixaban) – History

Aug 21, 2014	FDA Approves Eliquis (apixaban) for the Treatment of Deep Vein Thrombosis and Pulmonary Embolism
Mar 18, 2014	FDA Approves Eliquis to Reduce Risk of Blood Clots Following Hip Or Knee Replacement Surgery
Jul 11, 2013	FDA Accepts Eliquis (apixaban) Supplemental New Drug Application for Review for Prophylaxis of Deep Vein Thrombosis Following Hip Or Knee Replacement Surgery
Dec 28, 2012	FDA Approves Eliquis to Reduce the Risk of Stroke, Blood Clots in Patients with Non-Valvular Atrial Fibrillation

SOURCE

https://www.drugs.com/history/eliquis.html

ELIQUIS (apixaban) – Mechanism of action. Apixaban is a highly selective, orally bioavailable, and reversible direct inhibitor of free and clot-bound factor Xa. Factor Xa catalyzes the conversion of prothrombin to thrombin, the final enzyme in the coagulation cascade that is responsible for fibrin clot formation.

Apixaban (ELIQUIS) is a prescription medicine used to reduce the risk of stroke and blood clots in people who have atrial fibrillation, a type of irregular heartbeat, not caused by a heart valve problem (not adequately tested for mitral stenosis or mechanical valves, other valve issues were fine if valve thrombosis is not the concern).

ELIQUIS is a prescription medicine used to treat blood clots in the veins of your legs (deep vein thrombosis) or lungs (pulmonary embolism), and reduce the risk of them occurring again.

ELIQUIS is a prescription medicine used to reduce the risk of forming a blood clot in the legs and lungs of people who have just had hip or knee replacement surgery.

B. Antiplatelets Agents

Action and Use

1. Medications used to prevent or disrupt the aggregation of clusters of platelets needed to form a clot by inhibiting certain enzyme pathways to prevent clot formation
2. Used to treat thrombus formation, often used as adjunctive therapy to other anticoagulants i.e., warfarin (Coumadin)
3. Used as preventive and treatment measures for Patients with MI, Stroke, and cardiac surgery

Common Antiplatelets Medications:

• Aspirin (PO) is an antiplatelet agent is an analgesic, an anti-inflamatory and antipyretic agent
• Ticlopidine (Ticlid) (PO) used by patients that can’t take Aspirin
• Dipyridamole (Persantine) (PO) used in cardiac stress testing is an antiplatelet agent
• Clopidrogrel bisulfate (Plavix) (PO) used as secondary prevention for Patients that has an MI, stroke and peripheral artery disease (PAD)
• Abciximab (ReoPro) (IV – Bolus, Constant IV) is a fab fragment of a specific monoclonal antibody
• Eptifibatide (Integril) (2mcg/kg/min (IV)
• Tirofiban (Aggrastat) (0.1 mcg/kg/min (IV)

Contraindications:

• Aspirserious in is to be avoided in Pediatric population, in Patients with Asthma, GI Bleed, known intolerance to ASA
• Dipyridamole (Persantine) is contraindicated in pregnant an dlactating women
• Abciximab (ReoPro) for Patient with recent CVA, bleeding and thrombocytopenia
• Ticlopidine (Ticlid) in Patients with liver disease, evidence of blood dyscrasias, pregnant women and hypersensitivity to the drug
• Clopidrogrel bisulfate (Plavix) in Patients with peptic ulcer disease, intracranial hemorrhage and hypersensitivity to the drug

Drug interactions:

• Clopidrogrel bisulfate (Plavix) and NSAIDS – increase risk of bleeding
• Ticlopidine (Ticlid) can increase level of levels of theophylline and phenytoin. Cimetidine increases levels of Ticlid in the body
• Dipyridamole (Persantine) and Aspirin increase risk for bleeding
• With Aspirin: increased effects of ETOH, anticoagulants, methotrexate and sulfonylureas
• With Aspirin: decreased effects of Angiotensin Converting Enzyme (ACE) inhibitors, Beta Blockers and diuretics

Side effects: General – bruising, hematuria, tarry stools, blood dyscrasias, hemorrhage, GI symptoms, Nausea & Vomiting, dizziness, confusion

Ticlopidine (Ticlid) serious blood dyscrasias, i.e., agranulocytosis and neutropenia, jaundice, raise level of Cholesterol

Clopidrogrel bisulfate (Plavix) chest pain, edema, hypertension

Adverse effects:

Aspirin toxisity: tinnitus and ototoxicity, increase uric acid levels

Abciximab (ReoPro): allergic reaction

 

Other Antiplatelets Agents recently developed, see articles in the Book, i.e.,

Brilinta ticagrelor (Rx) History

PLATO Trial on ACS: BRILINTA (ticagrelor) better than Plavix® (clopidogrel bisulfate): Lowering chances of having another heart attack Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment What is the role of plasma viscosity in hemostasis and vascular disease risk?

Sep  3, 2015	FDA Approves Expanded Indication for Brilinta to Include Long-Term Use in Patients with a History of Heart Attack
Mar 30, 2015	FDA Approves New Crushing Option for the Administration of Brilinta
Jul 20, 2011	FDA approves blood-thinning drug Brilinta to treat acute coronary syndromes

SOURCE

https://www.drugs.com/history/brilinta.html

 

– Brilinta ticagrelor  – Acute Coronary Syndrome (ACS)

P2Y(12) platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with ACS (unstable angina, non-ST elevation MI, or ST elevation MI) or a history of MI

For at least the first 12 months following ACS, Brilinta ticagrelor is superior to clopidogrel (Plavix)

Ticagrelor also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS

 

C. Thrombolytics – are given in emergency at critical care units

C-1 Thrombus Dissolving Agents

Action and Use

1. Helps activate the fibrinolytic system that breaks down the thrombus or blood clot, it is activated naturally in the body to prevent excessive clotting or vascular compromise
2. Conversion of plasminogen to plasmin helped break down the clot by digesting fibrin and degrading fibrinogen and other procoagulant proteins into soluble fragments
3. Indications: Patients at risk for developing thrombus causing ischemia, i.e., Acute MI, arterial thrombosis, DVT, PE, and occlusion of catheters or shunts

Common Thrombolytic Medications:

• Alteplase (Activase) – IV [natural substance secreted by vascular endothelial cells in the body, therefore does not cause an antigenic response]
• Anistreplase (Eminase) – IV
• Reteplase (Retavase) – IV
• Streptokinase, Strepase) – IV[isolated from group-A beta-hemolytic streptococci (bacteria) is antigenic and systemic]
• Urokinase (Abbokinase Open-Cath) – IV[indicated for massive PE patients who has compensated hemodynamically]

Aminocaproic Acid (Amicar) is antidote to Streptokinase and Urokinase

Contraindications:

• IM administration – only IV
• In Patients who are activily bleeding, recent history of CVA, uncontrolled hypertension, recent trauma and Cancer
• During pregnancy

Drug interactions:

Increased risk of bleeding when taken with anticoagulant and antiplatelet drugs

Side effects: Hemorrhage, hypersensitivity reactions, Nausea and vomiting, hypotension, cardiac dysrhythmias

Adverse effects are dose-related: cardiac dysrhythmias in patients in acute state of disease

C-2 Hemostatic Agents

Action and Use

• Systemic hemostatics are substances that inhibit bleeding after an injury and reestablish homeostasis (hematologic balance)
• Used to stop or prevent bleeding
• Vitamin K works in the liver to formulate clotting factors (II, VII, IX and X) necessary for the coagulation cascade
• Vitamin K is mandatory protocol to prevent hemorrhagic disease in newborn

Common Systemic Hemostatic Medications:

• Aminocaproic Acid (Amicar) (PO) (IV)
• Aprotinin (Trasylol) (IV)
• Phytonadione – Vitamin K (oil soluble)
• Vitamin K1 (AquaMEPHYTON) (PO/SC/IM)
• Vitamin K4 (Menadiol sodium disphosphate (Synkayvite) (PO/SC/IM/IV)
• Tranexamic Acid (Cyklokapron) (25 mg/kg (PO)) (10mg/kg PostOPS (IV))

Contraindications:

• Amicar is contraindicated in patients with DIC, postpartum bleeding, UI bleeding or new burns
• Vitamin K is contraindicated during last weeks of pregnancy
• Vitamin K is contraindicated in patients with liver disease

Drug interactions:

• Amicar and Tranexamic Acid with estrogen and Oral contraceptives can lead to increased coagulation
• Amicar and certain antibiotics can lead to ototoxicity and nephrotoxicity
• Vitamin K is inhibited by antibiotic drugs changing GI bacterias and Mineral Oil decreases absorption of vitamin K

Side effects: Allergic reaction to Vitamin K products, GI disturbance, systemic and at injection site

Adverse effects dose related: Overdose of Vitamin K in newborns interferes with coagulation cascade

 

Other Systemic Hemostatic Medications: Clotting Factor Replacement Therapy

• Antihemophilic Factor (several products)
• Antithrombin III (Atnativ, Trombate III)
• Desmopressin (DDAVP, Stimate)
• Factor IX complex, human (Bebulin, Profilnin)
• Coagulation Factor IX, recombinant (Benefix)

 

D. Blood Modifying Agents: Medications to Lower Cholesterol

In the book there are numerous articles on this subject in Part One and in Part Two, therefore here they are only listed without additional drug information.

Common Lowering Cholesterol Medications:

D-1 – HMG-CoA Reductase Inhibitors, aka STATINS (PO)

• Atorvastatin (Lipitor)
• Cerivastatin (Baycol)
• Fluvastatin (Lescol)
• Lovastatin (Mevacor)
• Pravastatin (Pravachol)
• Simvastatin (Zocor)

D-2 – Fibric Acid Derivatives (PO)

• Clofibrate (Abitrate, Atromid-S)
• Fenofibrate (Tricor)
• Gemfibrozil (Lopid)

D-3 – Nicotinic acid

• Niacin, Vitamin B3 

D-4 – Estrogens – cardio protective Lowering LDL Increasing HDL in women: premenopausal, perimenopausal and postmenopausal

 

Class VIII. Antihypertensives, Antihypotensives, Diuretics, Potassium Supplementation – Renal Medications

Antihypertensives is the most widely drug class in use for treatment of the most severe epidemics in the US, related to elevated Blood Pressure caused by overweight and other comorbidities, chiefly Diabetes (DM2). Systemic management of blood pressure requires addressing multiple organs involvement and dysfunction leading to an increase in complex risks for cardiovascular diseases.

We covered, above all the Cardiac medications by

1. Action and Use
2. Common Medications
3. Contraindications
4. Drug interactions
5. Side effects
6. Adverse effects

The medications in the Class VIII category are presented by the following two descriptors, only, because the focus of the book is on Pharmaco-Therapy of Cardiovascular diseases. This Class VIII should be the focus of a book on Renal Medications and their effects on Cardiovascular disease management.

1. Action and Use
2. Common Medications 

Class VIII – Renal Medications, systemic pharmaco-therapy with positive effects on cardiovascular function

 

A. Diuretics

A-1     Loop diuretics – administered early in the day to avoid nocturia 

Action and Use:

• Agents that increase the amount of urine excreted, inhibit electrolyte reabsorption in the thick ascending loop of Henle, promote excetion of sodium, water, chloride and potassium 
• The antihypertensive action involves renal vasodilation to provide increase in the glomerular filtration rate (GFR) and a decrease in peripheral vascular resistance
• Loop diuretics are more potent than thiazide diuretics causing rapid diuresis resulting in decrease of vascular fluid volume, decrease in cardiac output and decrease in blood pressure
• Used in Patients with low GFR and hypertensive emergencies, if edema is present, CHF, Chronic Renal Failure (CRF) and hepatic cirrhosis
• May be used to increase renal elimination in case of overdose

Common Loop Diuretic Medications:

• Bumetanide (Bumex) [PO, IV]
• Ethacrynic acid (Edecrin) [PO, IV mg/kg}
• Furosemide (Lasix) [PO, IV]
• Toresemide (Demedex) [PO, IV]

 

A-2     Thiazide diuretics – administered PO 

Action and Use

• increase urinary excretion of sodium and water by inhibiting sodium reabsorption in the cortical diluting tubule of the kidney
• Hypotensive effect may be due to direct arteriolar vasodilation and decrease total peripheral resistance
• Used for edema and hypertension (elevation of systolic blood pressure >140mmHg and diastolic >90 mmHg)

Common Thiazide diuretics Medications:

Naturetin, Exna, Diucardin, Diuril, Microzide, Hygroton, thalitone, Hydrochlorothiazide (HCT), Esidrix, Hydrodiuril, lozol, Enduron, Xaroxylin, Minizide, Hydromox, Diurese

 

A-3     Potassium-sparing diuretics

Action and Use

• Act directly on the distal convoluted tubule to increase sodium excretion and decrease potassium secretion
• Used for hypertension and edema related to CHF
• Spironolactone is also used for detection of primary hyperaldosteronism, hirsutism and premenstrual syndrome, as off label uses

Common Potassium-sparing diuretics Medications: administered PO

• Amiloride (Midamor)
• Spironolactone (Aldactone)
• Triamterene

 

A-4     Carbonic anhydrase inhibitors 

Action and Use

• Reversible inhibition of the enzyme Carbonic anhydrase which promotes excretion of bicarbonate, sodium, potassium and water
• Used in treatment of edema caused by CHF
• Used for open angle glaucoma to decrease intraocular pressure
• Used to treat metabolic alkalosis

Common Carbonic anhydrase inhibitors Medications:

• Acetazolamide (Diamox)
• Dichlorphenamide (Daranide)
• Methazolelamide (Neptazane)

 

A-5     Osmotic diuretics – administered IV by slow infusion, not to be infused with blood or blood products 

Action and Use

• Increase osmotic pressure of glomerular filtrate in proximal tubule and loop of Henle inhibiting reabsorption of water and electrolytes, thus promoting diuresis
• Used to prevent and manage acute renal failure (ARF) and oliguria
• Used to decrease intraoccular and intra cranial pressure
• Mannitol is used with chemotherapy to induce diuresis

Common Osmotic diuretics Medications:

• Mannitol
• Urea

 

B. Potassium Supplements – Potassium is the main cation in body cells

Action and Use

• Maintains intracellular tonicity, balance with sodium across cell membranes, transmit nerve impulses mentain cellular metabolism
• Involved in contracting cardiac and skeletal muscle, maintain acid-base balance and normal renal function
• Potassium is absorbed from the GI tract and excreted largely by the kidneys
• Used to prevent and treat hypokalemia

Drug interactions:

• Anticholinergics and Potassium Supplements increase risk of GI irritation and ulceration
• Increase risk for hyperkalemia
• Not recommended for Patients with severe or complete heart block taking digitalis due to arrhythmias
• Risk for severe Hyperkalemia if used with Potassium-sparing diuretics, angiotensin converting enzyme (ACE) inhibitors (ACEI) or salt substitutes containing potassium salts

C. Antihypertensives for sustained elevation of systolic and/or diastolic blood pressure

C-1 See A. Diuretics, above

C-2 Adrenergic inhibitors (Alpha and Beta Blockers) 

Alpha Blockers

• Alpha-adrenergic blocking agents decrease vasomotor tone to cause vasodilation and thus reduce blood pressure
• Used for peripheral vascular disorders, hypertension and benign prostatic hyperplasia (BPH)
• Beta Blockers, See, Class II, above

Beta Blockers reduce Blood Pressure by preventing stimulation of the beta receptors in the heart by epinephrine and norepinephrine, thereby decreasing heart rate and cardiac outputInterfere with the release of renin by the kidneys to decrease the renin-angiotensin mechanism resulting in reduced Blood Pressure

Used for hypertension, angina, arrhythmia, glaucoma, myocardial infarction (MI) and migraine

Common Alpha Blockers Medications – Administered PO

• Prazosin (Minipress)
• Terazosin (Hytrin)
• Doxazosin (Cardura)
• Labetalol (Trandate/Normodyne)
• Carvedilol (Coreg)
• Common Beta-Adrenergic Blocker Medications: See, Class II, above
• Atenolol (Tenormin)– side effects: Bradycardia, Hypotension, worsening CHF, worsening PVD, Bronchospasm
• Sotalol – side effects: Impotence, GI upset, Increased triglycerides
• Metoprolol (Lopressor)– side effects: decrease HDL, mask signs of Hypoglycemia
• Nadolol (Corgard)
• Propranolol (Inderal)
• Timolol
• Acebutolol (Sectral)
• Betaxolol (Kerlone)
• Pindolol (Visken)

C-3  Angiotensin Converting Enzyme (ACE) Inhibitors – administered PO

Action and Use

• Inhibit the renin-angiotensin-aldosterone mechanism by blocking conversion of angiotensin I to angiotensin II and prevent peripheral vasoconstriction
• Used to treat hypertension – preferred drug for hypertensive Patients with diabetic nephropathy

Common Angiotensin converting enzyme (ACE) inhibitors Medications:

• Captopril (Capoten)
• Lisinopril (Prinivil)
• Enalapril (Vasotec)
• Ramipril (Altace)
• Benzapril (Lotensin)
• Fosinopril (Monopril) (BP decreases within 1 hour, peaks 2-6 hours)
• Quinapril (Accupril)
• Moexipril (Univasc)
• Trandolapril (Mavik)

 

C-4  AngiotensinII Receptor Blockers (ARBs), AngiotensinII antagonists – administered PO

Action and Use

• Antagonists at angiotensinII receptor of vascular smooth muscle blocking vasoconstriction and aldosterone-secreting effects
• Used for hypertension

Common AngiotensinII Receptor Blockers Medications:

• Losartan (Cozaar)
• Valsartan (Diovan)
• Olmesartan (Benicar)

 

C-5 Calcium Channel Blocker

Common Calcium Channel Blocker Medications, See Class III, above

• Amlodipine (Norvasc)
• Diltiazem (Cardizem, Dilacor RR and XR, Tiazac)
• Nifedipine (Adalat, Procardia) RR and SR
• Verapamil (Calan, Covera HS, Verelan, Isoptin) RR and SR

C-6 Peripheral Vasodilators, See above, Class IV and Class VIII

Common Peripheral Vasodilator Medications:

• Hydralazine HCL, See Class VIII, A-2, Thiazide diuretics
• Nitroprusside, See Class IV, Peripheral Vasodilators
• Prazosin, See Class VIII, C-2, Common Alpha Blockers

 

C-7 Other Antihypertensives – Anti-Adrenergic Medications, administered PO

 

C-7.1  Centrally Acting Sympatholytics

Action and Use

• Stimulate the Alpha 2 receptors in the central nervous system (CNS) to inhibit the sympathetic cardio-accelerator and vasoconstrictor centers
• Decrease sympathetic outflow from the CNS resulting in decrease the arterial pressure

Common Centrally acting Anti-Adrenergic Sympatholytics Medications:

• Clonidine (Catapres)
• Guanabenz (Wytensin)
• GuannFacine (TENEX)
• Methyldopa (Aldomet)

 

C-7.2  Peripheral Anti-Adrenergic Medications 

Action and Use

• Deplete catecholamine stores in the peripheral nervous system and perhaps in the CNS
• Decrease total peripheral resistance, heart rate, and cardiac output

Common Peripheral Anti-Adrenergic Medications:

• Reserpine (Serpasil)
• Guanadrel (Hylorel)

 

C-7.3  Hypertensive Emergency Medications, administered IV by infusion pump in critical care units

Action and Use

• Relax arteriolar smooth muscle causing vasodilation
• Reduce peripheral vascular resistance thus, decreasing Blood Pressure
• Used to treat hypertensive Crisis

Common Hypertensive Emergency Medications:

• Nitroprusside (Nipride) mcg/kg/min IV
• Nitroglycerin, mcg/min IV
• Diazoxode (Hyperstat), mg/kg IV
• Hydralazine (Vasodilator)
• Labetalol (Beta Blocker)
• Enalapril (ACEI)
• Furosemide and Nicardipine (Diuretics)

D. Antihypotensives (Sympathomimetics), administered IV

Action and Use

• Mimic the fight or flight response of the sympathetic nervous system, selectively stimulating alpha-adrenergic and beta-adrenergic receptors
• Stimulation of alpha-adrenergic receptors results in vasoconstriction and increase systemic BP
• Stimulation of beta-adrenergic receptors increases the force and rate of myocardial contraction
• Used to treat Shock 

Common Hypotensive Sympathomimetic Medications:

• Norepinephrine (Levophed), mcg/min IV
• Metaraminol (Aramine), mg IV
• Dopamine (Intropin), mcg/kg/min IV
• Dobutamine (Dobutrex), mcg/kg/min IV
• Isoproterenol (Isuprel), mg/min IV Infusion, IV Bolus, IM or SC (bronchospasm in Asthma patients)

Adverse effects of Hypotensive Sympathomimetic Medications:

1. Severe hypertension, anaphylaxis
2. Arrhythmias, cardiac arrest, ventricular tachycardia
3. Stokes-Adams seizures, Asthmatic episodes

SOURCES

1. Bertram G. Katzung, Basic & Clinical Pharmacology, Lange Medical Books, 9th Edition, McGraw-Hill, 2004. Chapters: 17, 18, 19, 34, 35, 36,
2. Suzanne Kay Marnocha, RN, CCRN, PhD, Cardiac Medications, in Pharmacology, Pearson/Prentice Hall, 2005
3. Daryle Wane, MS, APRN, BC, Blood Modifying Agents, in Pharmacology, Pearson/Prentice Hall, 2005
4. Julie A. Adkins, RN, MSN, FNP-C, Renal System Medications, in Pharmacology, Pearson/Prentice Hall, 2005

Part One

Cardiovascular Diagnoses and Pharmacological Therapy

 

Introduction to Part One by Justin D. Pearlman, MD, PhD, FACC 

Chapter 1: National Trends: Cardiovascular-related Hospital stay, Cost of Treatment & Societal Burden

Chapter 2: Introduction to Drug Types: De Novo Brand, Generic, Biologics, Biosimsilars Chapter 3: Anti-Inflammatory & Systemic Inflammatory

Chapter 4: Anti-thrombotic Drug Class & Novel Oral Anticoagulants (NOACs)

Chapter 5: Pharmaco-Genetics response to Congenital and Spontaneous Mutations: new drugs for Atherosclerosis, Genetic-related Novel Anti-Cholesterol, Lipids, LDL, HDL, Hypertriglyceridemia Hyperlipidemia

Chapter 6: Epigenetics, Gender differences and Life Style: DM, Obesity, Hormonal Markers, Diets, Chrono-therapeutics

Chapter 7: Blood Pressure Management: Genetics & Human Adaptive Immunity

Chapter 8: Anti-arrhythmic Drugs – Atrial Fibrillation (AF) & Silent Cerebral Infarctions

Chapter 9: MI, Acute Coronary Syndrome (ACS) and Heart Failure (HF)

Chapter 10: Calcium & Cardiovascular Diseases: Contractile Dysfunction, Calcium as Neurotransmitter Sensor

Chapter 11: Regeneration: Cardiac System (cardiomyogenesis) and Vasculature (angiogenesis)

Chapter 12: Vascular Biology, Atherosclerosis and Molecular Cardiology

Chapter 13: PharmacoGenomics in Cardiovascular Disease

Chapter 14: Drug Adverse Effects and Toxicity

Summary by Justin D. Pearlman, MD, PhD, FACC

Introduction to Part One by Justin D. Pearlman, MD, PhD, FACC

Part One of this curated Volume on pharmacologic management of cardiovascular disease examines the state of the art as summarized by current health care priorities, current cardiovascular medication classification and offerings, and in depth review of the achievements and limitations of current and anticipated future pharmaceutical therapies for cardiovascular disease. The current priorities adapt to cost benefit analysis of prevalent cardiovascular disorders, as limited resources are arguably best directed to where they will do the most good. The scope of that concern includes prevention as well as curtailment of severity of impairment, by improving out patient management, aiming at to alleviate suffering and achieve sufficient quality of life to avoid expensive hospitalizations, interference with productivity, and shortened lifespan. Major categories of cardiovascular disease are reviewed in separate chapters, based on distinct pathways and therapeutic considerations. The closing chapter addresses adverse effects of therapy. 

Chapter 1

National Trends: Cardiovascular-related Hospital stay, Cost of Treatment & Societal Burden

 

1.1 Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems

Curators: Justin D. Pearlman, MD, PhD, FACC, Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

THE VOICE OF Dr. Pearlman IS FOUND IN ITALICS BELOW.

A major growing cost of health care stems from heart failure which occurs from persisting damage from smoking, high blood pressure, diabetes, coronary disease, street drugs, viruses, obesity, sleep apnea, genetic disorders and arrhythmias. The following link presents a forecast from the American Heart Association for heart failure, discussion of genetic diseases affecting the heart, biomarkers, and persisting issues with hypertension, in particular, arterial stiffness. Heart failure is the greatest burden for the elderly, accounting for more hospitalizations than any other condition, and it is increasing in prevalence, at a current cost of $30.7 billion, and at 12 year forecast $69.8 billion/year.

The next link reviews Forecasting the Impact of Heart Failure in the United States : A Policy Statement From the American Heart Association;   A Case Study from the GENETIC CONNECTIONS Seeking Clues to Heart Disease in DNA of an Unlucky Family; Arterial Stiffness and Arterial Elasticity in Quest for a Drug Stabilizer: Isolated Systolic Hypertension, caused by Arterial Stiffening Ineffectively Treated by Vasodilatation Antihypertensives, and Clinical Decision Support Systems and Biomarkers of Cardiovascular Disease, Molecular Basis and Practical Considerations.

https://pharmaceuticalintelligence.com/2013/05/15/diagnosis-of-cardiovascular-disease-treatment-and-prevention-current-predicted-cost-of-care-and-the-promise-of-individualized-medicine-using-clinical-decision-support-systems-2/

 

1.2 National Trends, 2005 – 2011: Adverse-event Rates Declined among Patients Hospitalized for Acute Myocardial Infarction or Congestive Heart Failure

Reporter: Aviva Lev-Ari, PhD, RN

The discussion of trends in the link below addresses successes and failures of current practices as represented by adverse event rates for heart attacks, heart failure, pneumonia, and conditions requiring surgery 2005-2011. Outcomes improved for heart attacks and heart failure, but not for pneumonia or surgeries in general. The former may credit advances in timing and impact of treatment and secondary prevention (tobacco, diabetes, sleep apnea). Indiscriminate use of strong antibiotics may contribute to worsening treatment resistance affecting the latter two categories.

https://pharmaceuticalintelligence.com/2014/02/04/national-trends-2005-2011-adverse-event-rates-declined-among-patients-hospitalized-for-acute-myocardial-infarction-or-congestive-heart-failure/

 

1.3 Economic Toll of Heart Failure in the US: Forecasting the Impact of Heart Failure in the United States – A Policy Statement From the American Heart Association

The economic cost of heart failure, and future staffing needs, are addressed in the link below based on the American Heart Association forecasts. The analysis predicts a dire 3-fold rise in the cost of care by 2030, particularly from heart failure, unless new methods reduce the need for hospitalization and improve impact from outpatient visits.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/04/25/economic-toll-of-heart-failure-in-the-us-forecasting-the-impact-of-heart-failure-in-the-united-states-a-policy-statement-from-the-american-heart-association/

 

1.4 In Europe, BigData@Heart aim to improve patient outcomes and reduce societal burden of atrial fibrillation (AF), heart failure (HF) and acute coronary syndrome (ACS).

The link below examines how population data may drive improvements to reduce the cost of managing atrial fibrillation, heart failure, and acute coronary disease, stemming from a new collaboration in Europe between practitioners, epidemiologists, big data statisticians, pharmaceutical scientists and patient organizations called “BigData@Heart.”

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/07/10/in-europe-bigdataheart-aim-to-improve-patient-outcomes-and-reduce-societal-burden-of-atrial-fibrillation-af-heart-failure-hf-and-acute-coronary-syndrome-acs/

 

1.5 Cost per Inpatient Hospital Stay: Five cardiovascular issues ranked in the top 10 – #1 Heart valve disorders, #2 Acute myocardial infarction (heart attack), #4 Coronary atherosclerosis, #7 Septicemia, #10 Acute cerebrovascular disease

This next link ranks the biggest contributions to hospitalization costs, with heart valve disease at the top, averaging over $40,000 per visit.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/27/cost-per-inpatient-hospital-stay-five-cardiovascular-issues-ranked-in-the-top-10-1-heart-valve-disorders-2-acute-myocardial-infarction-heart-attack-4-coronary-atherosclerosis/

 

1.6 Differences in Health Services Utilization and Costs between Antihypertensive Medication Users Versus Nonusers in Adults with Diabetes and Concomitant Hypertension from Medical Expenditure Panel Survey Pooled Years 2006 to 2009

As reported below, use of antihypertensive medication by diabetics significantly reduces their need for costly hospitalization stays.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/28/differences-in-health-services-utilization-and-costs-between-antihypertensive-medication-users-versus-nonusers-in-adults-with-diabetes-and-concomitant-hypertension-from-medical-expenditure-panel-su-2/

 

1.7 Trends in HealthCare Economics: Average Out-of-Pocket Costs, non-Generics and Value-Based Pricing, Amgen’s Repatha and AstraZeneca’s Access to Healthcare Policies

The link below analyzes the push to generic and no-copay options for medication (now 30% of prescriptions are no co-pay), which, presumably due to competition, lowered out of pocket costs for both generic and brand pharmaceuticals. Average out-of-pocket cost dropped from $9.66 in 2013 to $8.47 in 2016 – from $6.05 to $5.54 for generics, and $32.36 to $28.13 for brand pharmaceuticals.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/05/04/trends-in-healthcare-economics-average-out-of-pocket-costs-non-generics-and-value-based-pricing-amgens-repatha/

 

1.8 The Cost to Value Conundrum in Cardiovascular Healthcare Provision

The following discusses the Affordable Care Act (ACA) impact on healthcare resources, community care, hospice and home care, on Medicaid, and decline in physician acceptance of Medicaid.

Author: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/01/01/the-cost-to-value-conundrum-in-cardiovascular-healthcare-provision/

 

Chapter 2

Introduction to Drug Types:

Brand, Generic, Biologics, Biosimsilars

 

2.1 Conceived: NEW Definition for Co-Curation in Medical Research

Curation, which I think of as a pleasant way to broach through a range of thought provoking topics with original sources made convenient and accessible, augmented by expert voices sorting wheat from chaff , is defined, explained and motivated in the links below.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/04/conceived-new-definition-for-co-curation-in-medical-research/

 

2.2 Cardiovascular Original Research: Cases in Methodology Design for Content Curation and Co-Curation

Further discussion of curation is presented with examples.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/07/29/cardiovascular-original-research-cases-in-methodology-design-for-content-curation-and-co-curation/

 

2.3 OPINION LEADERSHIP on Cardiovascular Diseases: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation – Epilogue to Volume Two

Further discussion around curation addresses facilitated access to the frontiers of medical science, with  critiques and synthesis of separate research findings. 

Author and Curator: Aviva Lev-Ari, PhD, RN, Editor-in-Chief, BioMed e-Series of e-Books

https://pharmaceuticalintelligence.com/2014/07/31/opinion-leadership-on-cardiovascular-diseases/

 

2.4 The Young Surgeon and The Retired Pathologist: On Science, Medicine and HealthCare Policy – The Best Writers Among the WRITERS

Commentaries on two contributors to science illustrate the value of following a curator’s interest and voice identifying salient information that otherwise might not reach your attention. Two physicians receive a hightlight here.

• One is Atul Guwande,@Atul_Gawande ‏Surgeon @BWH, Writer, Researcher, Dilettante. https://www.ariadnelabs.org/  http://www.lifebox.org/  atulgawande.com  a keynote HIMSS19 https://drumup.io/s/F9UIuM  #Sociaall

(New Yorker Magazine, and best sellers), and public health researcher who recently was selected to serve as CEO of the healthcare venture from Amazon, Berkshire Hathaway and JPMorgan Chase.

• The second is Larry Bernstein, a curator of this forum and Co-Editor of this Volume, and former Chief of the Division of Clinical Pathology (Laboratory Medicine) at  New York Methodist Hospital-Weill Cornell Affiliate.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/10/the-young-surgeon-and-the-retired-pathologist-on-science-medicine-and-healthcare-policy-best-writers-among-the-writers/

 

2.5 Ethical Considerations in Studying Drug Safety — The Institute of Medicine Report


The following curation focuses on ethics issues and flaws in the USA drug safety regulation that were thrust to attention from the heated public debate about the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial, which compared the cardiovascular outcomes of long-term treatment with rosiglitazone with those of pioglitazone (Actos, Takeda) in patients with type 2 diabetes.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/23/ethical-considerations-in-studying-drug-safety-the-institute-of-medicine-report/

 

2.6 Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers

Intellectual property laws influence the profits that motivate creation of new medications as well as profit losses but price lowering impact of distinct but similar medications and generics. The generic  competition provisions of the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Act) apply to products approved under the Food, Drug, and Cosmetic Act, which include small molecule pharmaceuticals, but not to products approved under the Public Health Service Act, which include biologics. Since biologics are projected to become half of the biopharmaceutical market, there are mounting calls for a biosimilar pathway for companies obtaining Food and Drug Administration (FDA) approval of generic versions of existing biologics based upon lesser showings of safety and efficacy than is required for a pioneer biologic.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/07/30/biosimilars-intellectual-property-creation-and-protection-by-pioneer-and-by-biosimilar-manufacturers/

 

2.7 Biosimilars: Financials 2012 vs. 2008

The US government has been critical of the 12-year data exclusivity period for Pioneer Innovators, calling for it to be shortened to 7 years (12 years is favorable to Pioneer Innovators and less favorable for Biosimilar manufacturers). The status of the Affordable Care Act affects the status of regulations that set the balance between profits for innovators vs competitive price reduction.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/07/30/biosimilars-financials-2012-vs-2008/

 

2.8 Biosimilars: CMC Issues and Regulatory Requirements

Education forums address the rapid expansion of protein therapeutics into all major disease classes (cancer, metabolic disease, inflammatory disease, infectious disease, immune disorders, etc.), with particular attention to impact on quality and the ability to characterize and control product characteristics.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/07/29/biosimilars-cmc-issues-and-regulatory-requirements/

 

2.9 In One-Hour: A Diagnosis of Heart Attack made possible by one Blood Test

Curator Larry Bernstein draws attention to changes in the Troponin testing for heart attack addressed by TRAPID-AMI, a prospective observational study supported by Roche and investigated more than 1,200 patients with acute chest pain during 2011-2014.

Reporter: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/01/14/in-one-hour-a-diagnosis-of-heart-attack-made-possible-by-one-blood-test/

 

2.10 Daily Highlights at 2017 American Heart Association Annual Meeting Scientific Sessions

Curator Aviva Lev-Ari summarizes highlights from the AHA Annual Meeting, including take-home summary results of late breaking clinical trials of statins, cholesterol injection medications, blood pressure control, surgery for obesity, and other topics, with links to original speaker slide presentations.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/11/14/daily-highlights-at-2017-american-heart-association-annual-meeting-scientific-sessions/

 

2.11 2017 American Heart Association Annual Meeting: Sunday’s Science at #AHA17

Reporter, Aviva Lev-Ari, PhD, RN points out some additional highlights:

• TRiCS III – What differences were seen in cardiac surgery outcomes with restrictive red cell transfusion vs a more liberal strategy?

• DACAB – Which was better for CABG saphenous vein graft patency at one year: Ticagrelor + ASA or ASA alone?

• BRUISE CONTROL-2 – In AF patients, did different NOAC anticoagulant strategies change outcomes?

• PRESERVE – To prevent adverse outcomes after angiography, what were the benefits of using sodium bicarbonate or N-Acetylcysteine?

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/11/13/2017-american-heart-association-annual-meeting-sundays-science-at-aha17-presidential-address/

 

2.12 REAL TIME Highlights and Tweets: Day 1,2,3: World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

Curator Aviva Lev-Ari flags interesting presentations from the World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA, including $10,000 competition presentations from nineteen rising stars from Brigham Health and Massachusetts General Hospital of  their discoveries and insights thought to be disruptive of cardiovascular care of the future, for investors, leaders, donors, entrepreneurs and investigators and others who share a passion for identifying emerging high-impact technologies.

Author and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/05/03/deliverables-day-123-world-medical-innovation-forum-cardiovascular-%E2%80%A2-may-1-3-2017-boston-ma-httpsworldmedicalinnovation-orgagenda-highlights-of-live-day-1-world-medical/

 

2.13 Tweets by @pharma_BI and @AVIVA1950 at World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

Attendees had a wide range of take-home messages captured in their tweets about the forum.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/05/05/tweets-by-pharma_bi-and-aviva1950-at-world-medical-innovation-forum-cardiovascular-%E2%80%A2-may-1-3-2017-boston-ma/

 

2.14 e-Proceedings for Day 1,2,3: World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

A digest of presentations from around the world address thoughts on who will pay for what, and why.

Curator and Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/05/05/e-proceedings-for-day-123-world-medical-innovation-forum-cardiovascular-%E2%80%A2-may-1-3-2017-boston-ma/

 

2.15 Shaun Coughlin from UCSF Cardiovascular Research Center to cardio group for the Novartis Institute for Biomedical Research in Cambridge, MA

The dean of the UCSF med school, Talmadge King, lauds Coughlin’s “research discoveries revealed a mechanism by which proteases regulate cellular behaviors including a key mechanism that controls blood platelet activation and clot formation. This work led to a new medical therapy for preventing heart attacks and strokes. 

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/08/17/shaun-coughlin-from-ucsf-cardiovascular-research-center-to-cardio-group-for-the-novartis-institute-for-biomedical-research-in-cambridge-ma/

 

2.16 Expedite Use of Agents in Clinical Trials: New Drug Formulary Created – The NCI Formulary is a public-private partnership between NCI, part of the National Institutes of Health, and pharmaceutical and biotechnology companies

The NCI Formulary is a public-private partnership between NCI, part of the National Institutes of Health, and pharmaceutical and biotechnology companies, in support of the “Cancer Moonshot” initiative of Joseph Biden, to expedite the start of clinical trials by alleviating the lengthy negotiation process — sometimes up to 18 months — that had been required for investigators to access such agents on their own.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/01/12/expedite-use-of-agents-in-clinical-trials-new-drug-formulary-created-the-nci-formulary-is-a-public-private-partnership-between-nci-part-of-the-national-institutes-of-health-and-pharmaceutical-and/

 

2.17 Mechanisms of Drug Resistance

Many infectious diseases are increasingly difficult to treat because organisms have learned how to resist antibiotics, with some now resistant to all known therapies. Resistance is a serious progressive issue for HIV infection, staphylococcal infection, tuberculosis, influenza, gonorrhea, candida infection, and malariaThe underlying sciences of metabolomics and the essential role of genomic and epigenetic mechanisms guide the development of proteomic driven effectors of resistance to drug therapy.

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/10/09/mechanisms-of-drug-resistance/

Chapter 3

Anti-Inflammatory & Systemic Inflammatory

 

3.1 A new mechanism of action to attack in the treatment of coronary artery disease (CAD), Novartis developed Ilaris (canakinumab), a human monoclonal antibody targeting the interleukin-1beta innate immunity pathway

C-reactive Protein (CRP), an inflammation marker, is linked to risk of heart attack and stroke independent of lipids. Crestor can lower it but with risk of elevating glucose. In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), 150 mg of canakinumab every 3 months reduced high-sensitivity C-reactive protein (hs-CRP) levels by an average of 37% compared with placebo and achieved a 15% reduction in cardiovascular events — mostly MIs — compared with placebo. A follow up study by Paul Ridker et al [Lancet vol 392, issue 10118 2/2018] achieved >30% reduction in cardiovascular deaths for those achieving CRP<2.0.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/04/06/a-new-mechanism-of-action-to-attack-in-the-treatment-of-coronary-artery-disease-cad-novartis-developed-ilaris-canakinumab-a-human-monoclonal-antibody-targeting-the-interleukin-1beta-innate-i/

 

3.2 Long-term Canakinumab Treatment Lowering Inflammation Independent of Lipid Levels for Residual Inflammatory Risk Benefit – Personalized Medicine for Recurrent MI, Strokes and Cardiovascular Death

Here is another link to discussion of the CANTOS trial showing benefit of getting CRP below 2 g/dL (previously shown beneficial via Crestor in the JUPITOR TRIAL NEJM 2008) – this provides more evidence for benefit to risk of heart attack by suppressing the inflammation that plays a major role in unstable plaque.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/11/21/long-term-canakinumab-treatment-lowering-inflammation-independent-of-lipid-levels-for-residual-inflammatory-risk-benefit-personalized-medicine-for-recurrent-mi-strokes-and-cardiovascular-death/

 

3.3 Systemic Inflammatory Diseases as Crohn’s disease, Rheumatoid Arthritis and Longer Psoriasis Duration May Mean Higher CVD Risk

Patients with other inflammatory conditions treated with methotrexate likewise reduce their risk of heart attacks.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/10/09/systemic-inflammatory-diseases-as-crohns-disease-rheumatoid-arthritis-and-longer-psoriasis-duration-may-mean-higher-cvd-risk/

 

3.4 Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.

PLAC is a test measuring Lp-PLA₂  (lipoprotein-associated phospholipase A₂), a vascular-specific inflammatory enzyme implicated in the formation of rupture-prone plaque. It is approved by FDA and MEDICARE to assess inflammatory risk for coronary heart disease and ischemic stroke associated with atherosclerosis. If it is abnormal, and hs-CRP>2, consider canakinumab.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/30/cardiovascular-risk-inflammatory-marker-risk-assessment-for-coronary-heart-disease-and-ischemic-stroke-atherosclerosis/

 

Chapter 4

Anti-Thrombotic Drug Class & Novel Oral Anticoagulants (NOACs)

 

4.1 Coagulation Therapy: Leading New Drugs – Efficacy Comparison

This curation discusses various anticoagulants (“blood thinners”), including apixaban (Eliquis), which proved to be safer and more effective than Coumadin, but it has not been tested or approved for mitral stenosis or mechanical heart valves. When ads discuss “non-valvular AFIB” they mean not due to mitral stenosis, and when they say not for patients with “artificial heart valves” they mean mechanical valves.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/05/10/coagulation-therapy-leading-new-drugs-efficacy-comparison/

 

4.2 Is Pharmacogenetic-based Dosing of Superior for Anticoagulation Control?

Although attention to genotype should, in theory, be helpful or at least not harmful to estimating optimal dosing, it not only did not help achieve INR targets with Coumadin, it fared worse for black patients.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/04/is-pharmacogenetic-based-dosing-of-warfarin-superior-for-anticoagulation-control/

 

4.3 Apixaban (Eliquis): Mechanism of Action, Drug Comparison and Additional Indications

This curation reviews clinical trials and FDA machinations for the approval of apixaban (Eliquis) for clot treatments (pulmonary emboli, atrial fibrillation, DVT).

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/05/10/apixaban-eliquis-mechanism-of-action-drug-comparison-and-additional-indications/

4.4 FDA Approval marks first presentation of bivalirudin in frozen, premixed, ready-to-use formulation

This is the announcement from Baxter Pharmaceuticals of the FDA approval for the anticoagulant bivalirudin.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/01/24/fda-approval-marks-first-presentation-of-bivalirudin-in-frozen-premixed-ready-to-use-formulation/

 

4.5 Advantages and Disadvantages of Novel Oral Anticoagulants (NOACs)

This curation discusses and compares different oral anticoagulants. Overall, apixaban (Eliquis) is rising to the fore when it comes to safety and efficacy. It is very similar to rivaroxaban (Xarelto) except for the manufacturer decision to follow its half-life for twice daily dosing instead of imposing a  4x dose to coast through once a day dosing  with higher bleeding risk (choice made for Xarelto). Both have been criticized for not having a specific antidote (not a practical issue, the 12 hour half-life wears off before most patients would get access to an antidote) but now that issue is resolved with FDA approval of Portola Pharmaceuticals’ Andexxa, the first factor Xa inhibitor antidote indicated for patients treated with rivaroxaban (Xarelto) and apixaban (Eliquis), when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/03/20/advantages-and-disadvantages-of-novel-oral-anticoagulants-noacs/

 

4.6 Acute Coronary Syndrome (ACS): Strategies in Anticoagulant Selection: Diagnostics Approaches – Genetic Testing Aids vs. Biomarkers (Troponin types and BNP)

Biomarkers are emerging as guides to medical decisions ranging from earlier detection of MI or heart failure to recognition of who should receive prasugrel or ticagrelor after a heart attack, stroke and/or stent, instead of clopidogrel (PLAVIX).

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/03/13/acute-coronary-syndrome-acs-strategies-in-anticoagulant-selection-diagnostics-approaches-genetic-testing-aids-vs-biomarkers-troponin-types-and-bnp/

 

4.7 The presence of any Valvular Heart Disease (VHD) did not influence the comparison of Dabigatran [Pradaxa, Boehringer Ingelheim] with Warfarin

The RE-LY Trial took back some of the simple-minded assertions about “non-valvular” atrial fibrillation by showing it made no difference whether there was valve disease, other than still having trial exclusion of moderate to severe mitral stenosis.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/08/16/the-presence-of-any-valvular-heart-disease-vhd-did-not-influence-the-comparison-of-dabigatran-pradaxa-boehringer-ingelheim-with-warfarin/

 

4.8 Cangrelor wins Clopidogrel (Plavix): reduction of Risk of a composite of all-cause mortality, myocardial infarction, ischemia driven revascularization, and stent thrombosis

The most popular anti-platelet agent after aspirin to keep stents open is Plavix, but some patients are resistant to it, so cangrelor, like ticagrelor, has advantages. This curation points to FDA machinations leading to the approval of cangrelor, with the recognition of value: “in patients in whom treatment with an oral P2Y₁₂ platelet inhibitor prior to PCI is not feasible and when glycoprotein IIb/IIIa receptor antagonists are not anticipated to be used.” 

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/04/16/cangrelor-wins-clopidogrel-plavix-reduction-of-risk-of-a-composite-of-all-cause-mortality-myocardial-infarction-ischemia-driven-revascularization-and-stent-thrombosis/

 

4.9 Intracranial Vascular Stenosis: Comparison of Clinical Trials: Percutaneous Transluminal Angioplasty and Stenting (PTAS) vs. Clot-inhibiting Drugs: Aspirin and Clopidogrel (dual antiplatelet therapy) – more Strokes if Stenting

Next is a summary of the Cochrane review showing aspirin helps prevent repeat stroke, clopidogrel (PLAVIX) adds more protection but also more bleed risk without net mortality benefit, and stents alone are not as good.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/15/intracranial-vascular-stenosis-comparison-of-clinical-trials-percutaneous-transluminal-angioplasty-and-stenting-ptas-vs-clot-inhibiting-drugs-aspirin-and-clopidogrel-dual-antiplatelet-therapy/

 

4.10 Do Novel Anticoagulants Affect the PT/INR? The Cases of XARELTO (rivaroxaban) or PRADAXA (dabigatran)

Anticoagulants have some surprises including falsifying results from the standard INR test used for anticoagulation status, trials curtailed due to excess bleeding, and Xarelto dosing at odds with its half-life, sacrificing risk to attain claim of once a day dosing.

Curators: Lal, V., Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/23/do-novel-anticoagulants-affect-the-ptinr-the-cases-of-xarelto-rivaroxaban-and-pradaxa-dabigatran/

 

4.11 PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity

In addition to discovery of new biomarkers, there is also new uses of old markers. Sedementation Rate (ESR) displaced fibrinogen as an indicator of inflammation, now sed rate is largely used to track status of rheumatoid arthritis, giant cell arteritis and polymyalgia rheumatic. A new study suggests a new use for fibrinogen: An elevated serum fibrinogen level predicted worse short-term ischemic outcomes among patients undergoing elective percutaneous coronary intervention after pretreatment with clopidogrel.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/10/pci-outcomes-increased-ischemic-risk-associated-with-elevated-plasma-fibrinogen-not-platelet-reactivity/

 

4.12 Warfarin and Dabigatran, Similarities and Differences

Although apixaban (ELIQUIS) is now leading as safer and more effective than Coumadin for most uses (other than mechanical heart valves), there are multiple competitors, and insurance co-pay sometimes promotes alternatives. This curation discusses chemical details of dabigatran (PRADAXA) as an alternative to Coumadin (warfarin).

Author and Curator: Danut Dragoi, PhD

https://pharmaceuticalintelligence.com/2016/04/04/warfarin-and-dabigatran-similarities-and-differences/

 

4.13 Zontivity (vorapaxar), Merck’s Cardio Drug Approval by FDA: Will it Challenge existing Oral Anticoagulation drugs: i.e., Apixaban, Dabigatran, Edoxaban, Rivaroxaban

Vorapaxar/ZONIVITY is an anti-platelet agent (like aspirin, clopidogrel /PLAVIX, ticagrelo/BRILINTA), designed to decrease the tendency of platelets to clump together to form a blood clot, to decrease the risk of stent occlusion, heart attack and stroke. It is the first in a new class of drug, called a protease-activated receptor-1 (PAR-1) antagonist. In general, platelet inhibitors help unstable plaque and arterial obstruction, but markedly increase the risk of a major bleed for patients on anticoagulants (like apixaban/ELLIQUIS, or dabigatran/PRADAXA) which are prescribed for atrial fibrillation, atrial flutter, deep vein thrombosis (DVT), and pulmonary emboli. Coumadin, which is also an anticoagulant, is the only oral anticoagulant tested and approved for mechanical heart valves. 

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/05/10/zontivity-vorapaxar-mercks-cardio-drug-approval-by-fda-will-it-challenge-existing-oral-anticoagulation-drugs-i-e-apixaban-dabigatran-edoxaban-rivaroxaban/

 

4.14 United States Department of Justice closed investigation into AstraZeneca’s PLATO, Clinical Trial with Brilinta (ticagrelor)

BRILINTA plus aspirin was shown to be clinically more effective than clopidogrel plus aspirin in reducing thrombotic CV events, including CV death, at 12 months, based on data from the PLATO trial. The US Department of Justice opened and closed an investigation on concerns raised about that drug trial. The FDA originally took an extended period of time to review the pivotal PLATO study before approving the antiplatelet drug. The trial results have been dogged by questions regarding why there was a trend toward worse outcomes with ticagrelor vs clopidogrel at North American sites, which subsequently have been attributed to the dosage of aspirin (now limited to 81 mg when taking ticagrelor/BRILINTA).

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/09/03/united-states-department-of-justice-closed-investigation-into-astrazenecas-plato-clinical-trial-with-brilinta-ticagrelor/

 

4.15 PINNACLE Patients: Inappropriate Prasugrel (Effient, Lilly/Daiichi Sankyo) Use in “One in Five”: Prior Stroke or TIA can increase the risk of Bleeding

PINNACLE was a double-blind, randomized trial with 30 months follow up on 7243 patients under the age of 75 years receiving aspirin with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/06/10/pinnacle-patients-inappropriate-prasugrel-effient-lillydaiichi-sankyo-use-in-one-in-five-prior-stroke-or-tia-can-increase-the-risk-of-bleeding/

 

4.16 Outcomes in High Cardiovascular Risk Patients: Prasugrel (Effient) vs. Clopidogrel (Plavix); Aliskiren (Tekturna) added to ACE or added to ARB

The WOEST study  (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulantion and Coronary Stenting) suggested that omitting aspirin in patients with elevated bleeding risks leads to less bleeding and does not increase the risk of stent thrombosis, stroke or myocardial infarction. It was a study of just 573 patients randomized to triple therapy or dual therapy of an anticoagulant plus clopidogrel for at least one month after implantation of a bare-metal stent or one year after a drug-eluting stent; two-thirds of the patients were receiving oral anticoagulation for atrial fibrillation.

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2012/08/27/outcomes-in-high-cardiovascular-risk-patients-prasugrel-effient-vs-clopidogrel-plavix-aliskiren-tekturna-added-to-ace-or-added-to-arb/

 

4.17 What is the role of plasma viscosity in hemostasis and vascular disease risk?

Injury to the inner lining of arteries (endothelium) promotes deposition of cholesterol lipids in arteries (by active re-assembly). The role of “sheer forces” and fluid viscosity is discussed here, as a possible avenue of protection from strokes and heart attacks.

Curators: Larry, H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2012/11/28/what-is-the-role-of-plasma-viscosity-in-hemostasis-and-vascular-disease-risk/

 

4.18 Anticoagulation Genotype guided Dosing

Coumadin is the only approved oral blood thinner to protect patients with mechanical heart valves from sudden thrombosis and death (it depletes vitamin K which the liver uses in coagulation factors VII, IX, X, II, as well as protein factors S, C and Z). Comadin (warfarin) is also still used for blood clots, pulmonary emboli, atrial fibrillation and atrial flutter, though apixaban/ELIQUIS is getting wider use in those conditions, as it has proved to be safer and more effective. Genetic markers (CYP2C9 and VKORC1) may identify patients with higher bleed risk to help avoid complications and make safer choices.

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/12/08/anticoagulation-genotype-guided-dosing/

Chapter 5

Pharmaco-Genetics Drug Development Response to Congenital and Spontaneous Mutations: New Drugs for Atherosclerosis, Genetic-related Novel Anti-Cholesterol, Lipids, LDL, HDL, Hypertriglyceridemia, Hyperlipidemia

WATCH VIDEO  – Courtesy of YouTube as well as the individual sponsors of the links cited below.

Dr. Eric Berg likes natural sources of vitamin C, vegetables for K1 and K2, and low carbohydrates/insulin drive. He provides simple explanations for his views that most non-medical people can easily understand.

Treating Atherosclerosis – Dr. Harry Leonard Bush, Jr.

VIDEO: Treat Arteriosclerosis

 

5.1 Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

This curation reviews 348 articles that appeared in AHA’s Circulation Cardiovascular Genetics, between 3/2010 – 3/2013, classified into the following categories: Preventative Cardiology, MicroRNA in Serum as Biomarker for Cardiovascular Pathologies, Genetic Determinants of Potassium Sensitivity and Hypertension, Heart and Aging Research in Genomic Epidemiology, Genomics of Ventricular arrhythmias, Genetics of CVD and Hyperlipidemia, Genetics and Vascular Pathologies and Platelet Aggregation, Genomics and Valvular Disease, Heredity of Cardiovascular Disorders, and Pharmacogenomics.

Curators: Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/03/07/genomics-genetics-of-cardiovascular-disease-diagnoses-a-literature-survey-of-ahas-circulation-cardiovascular-genetics-32010-32013/

 

5.2 Voices from the Cleveland Clinic: On the New Lipid Guidelines and On the ACC/AHA Risk Calculator

This curation examines the Lipid Guidelines and ACC/AHA Risk Calculator, with commentaries from the Cleveland Clinic.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/21/voices-from-the-cleveland-clinic-on-the-new-lipid-guidelines-and-on-the-accaha-risk-calculator/

 

5.3 Congenital Heart Disease (CHD) at Birth and into Adulthood: The Role of Spontaneous Mutations

This next topic reviews congenital heart disorders, both those that turn babies blue, or

• Cyanotic (Ebstein’s anomaly, Hypoplastic left heart, Pulmonary atresia, Tetralogy of Fallot, Total anomalous pulmonary venous return, Transposition of the great vessels, Tricuspid atresia, Truncus arteriosus) and
• Non-cyanotic (Aortic stenosis, Atrial septal defect, Atrioventricular canal, Coarctation of the aorta, Patent ductus arteriosus, Pulmonic stenosis, Ventricular septal defect).

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/09/congenital-heart-disease-at-birth-and-into-adulthood-the-role-of-spontaneous-mutations-the-genes-and-the-pathways/

 

5.4 Harnessing New Players in Atherosclerosis to Treat Heart Disease

This curation examines the causes of hardening and blockage of arteries to stimulate thought about all avenues of diagnosis and medical management of this pervasive leading cause of debility and death, not just by lowering LDL and raising HDL, and suppressing inflammation, by focus on the roles of white blood cells and endothelial cells in the disease.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/04/25/harnessing-new-players-in-atherosclerosis-to-treat-heart-disease/

 

5.5 There may be a genetic basis to CAD and that CXCL5 may be of therapeutic interest

 Jonathan Schisler and colleagues at the University of North Carolina reported that people with clear arteries had markedly higher levels of the inflammatory mediator protein CXCL5, a small cytokine belonging to the CXC chemokine family that is also known as epithelial-derived neutrophil-activating peptide 78 (ENA-78), as well as genetic variants near the CXCL5 gene, compared with people with more plaque. This may serve as a biomarker, and may lead to a possible therapy (mimicking or stimulating the gene product).

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/09/there-may-be-a-genetic-basis-to-cad-and-that-cxcl5-may-be-of-therapeutic-interest/

5.6 Novel Anti-Cholesterol Drugs for Patients with Refractory Response to Statin derived from Familial persistent Hypercholesterolemia implicated by Genetics

Two new injectable treatments (1-2 times per month) improve bad cholesterol much better than statins and with much less limitation from muscle ache.

 

5.6.1 Praluent – FDA approved as Cholesterol-lowering Medicine for Patient non responsive to Statin due to Genetic origin of Hypercholesterolemia

There are now two approved medications that are more powerful than statins for patients with high LDL – Praluent and Repatha. Both work by blocking a protein called PCSK9, which interferes with the body’s ability to clear artery-damaging cholesterol from the blood. Patients with LDL >160 may drop to <70 by self injection once or twice a month.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/07/27/praluent-fda-approved-as-cholesterol-lowering-medicine-for-patient-non-responsive-to-statin-due-to-genetic-origin-of-hypercholesterolemia/

 

5.6.2 PCSK9: A Recent Discovery in Understanding Cholesterol Regulation @ AMGEN Cardiovascular

Early studies of PCSK9 inhibitors showed incremental improvement for patients taking both a statin and the controversial cholesterol GI uptake inhibitor ezetimide (controversial because it has not been shown to reduce mortality like other modes of improving LDL). In use alone or with a statin, many patients now enjoy much more dramatic improvements taking by a special injector system either 140 mg every 2 weeks, or 420 mg once a month. 

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/08/04/pcsk9-a-recent-discovery-in-understanding-cholesterol-regulation-amgen-cardiovascular/

 

5.6.3 Reversing Heart Disease: Combination of PCSK9 Inhibitors and Statins – Opinion by Steven Nissen, MD, Chairman of Cardiovascular Medicine at Cleveland Clinic

This looks at cost and effect: $14,100/year for evolocumab/REPATHA and $14,600/year for alirocumab/PRALUENT. The marked improvements in LDL are accompanied by imaging evidence of reduction/reversal of atherosclerosis.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/29/reversing-heart-disease-combination-of-pcsk9-inhibitors-and-statins-opinion-by-steven-nissen-md-chairman-of-cardiovascular-medicine-at-cleveland-clinicopinion-on-reversing-heart-disease-combinat/

 

5.6.4 Cholesterol Lowering Novel PCSK9 drugs: Praluent [Sanofi and Regeneron] vs Repatha [Amgen] – which drug cuts CV risks enough to make it cost-effective?

Costly life-saving drugs stimulate discussion of dollars vs lives (cost-effectiveness).

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/03/12/cholesterol-lowering-novel-pcsk9-drugs-praluent-sanofi-and-regeneron-vs-repatha-amgen-which-drug-cuts-cv-risks-enough-to-make-it-cost-effective/

 

5.6.5 FDA approval on 12/1/2017 of Amgen’s evolocumb (Repatha) a PCSK9 inhibitor for the prevention of heart attacks, strokes, and coronary revascularizations in patients with established cardiovascular disease

Here is a presentation of the FDA approvals for evolocumb/REPATHA.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/12/01/fda-approval-on-12-1-2017-of-amgens-evolocumb-repatha-a-pcsk9-inhibitor-for-the-prevention-of-heart-attacks-strokes-and-coronary-revascularizations-in-patients-with-established-cardiovascular-di/

 

5.6.6 PCSK9 inhibitors: Reducing annual drug prices from more than $14 000 to $4536 would be necessary to meet a $100 000 per QALY threshold per JAMA

Further analysis of dollars vs lives (cost effectiveness) computes the cost per “QALY” or quality life-years gained.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/08/17/pcsk9-inhibitors-reducing-annual-drug-prices-from-more-than-14%E2%80%AF000-to-4536-would-be-necessary-to-meet-a-100%E2%80%AF000-per-qaly-threshold-per-jama/

 

5.6.7 Efficacy and Tolerability of PCSK9 Inhibitors by Patients with Muscle-related Statin Intolerance – New Cleveland Clinic study published in JAMA 4/2016

Muscle ache is the most common reason patients stop taking a statin. However, often it is due to coQ10 deficiency, solvable by taking vitamin coQ10 100 mg daily. Also, even though the muscle ache is common to all statins, as well as to the GI uptake inhibitor ezetimibe/ZETIA, it is not a class effect, which means if you try all the statins, one may be tolerated very well. For those who cannot tolerate any statin, the more expensive injections are not only very effective, but they are generally better tolerated. The Rausse-3 Clinical Trial at the Cleveland Clinic found that muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients but the active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and only 1 of 145 evolocumab-treated patients (0.7%).

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/04/03/efficacy-and-tolerability-of-pcsk9-inhibitors-by-patients-with-muscle-related-statin-intolerance-new-cleveland-clinic-study-published-in-jama-42016/

 

5.6.8 ODYSSEY Outcomes trial evaluating the effects of a PCSK9 inhibitor, alirocumab, on major cardiovascular events in patients with an acute coronary syndrome to be presented at the American College of Cardiology meeting on March 10, 2018

Before criticizing the results of a large trial, it is interesting to look at the early stages of a trial design, for example, ODYSSEY Outcomes trial evaluating the effects of a PCSK9 inhibitor, alirocumab/PRALUENT, on major cardiovascular events in patients. Is the patient group tested representative of the question? Are the relevant outcomes measured for a long enough period? If you start with patients with minor abnormalities, or low risks for other reasons, or use low treatment doses, or short observation periods, you can miss out on benefits.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/28/odyssey-outcomes-trial-evaluating-the-effects-of-a-pcsk9-inhibitor-alirocumab-on-major-cardiovascular-events-in-patients-with-an-acute-coronary-syndrome-to-be-presented-at-the-america/

 

5.6.9 SNPs in apoE are found to influence statin response significantly. Less frequent variants in PCSK9 and smaller effect sizes in SNPs in HMGCR

Genetic testing can be risky to an individual (it may be sold to insurance companies to hike costs of insurance) because it identifies variations of genes and gene products that affect outcomes. This curation looks at genetic studies on 5745 individuals from the Treating to New Targets (TNT) trial with whole-genome and candidate gene analyses to identify gene associations affecting the response to atorvastatin treatment, to clarify why people differ in the benefits from a statin. The answers can lead to new treatments, including methods to resolve the issue for those who are resistant.

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/01/02/snps-in-apoe-are-found-to-influence-statin-response-significantly-less-frequent-variants-in-pcsk9-and-smaller-effect-sizes-in-snps-in-hmgcr/

 

5.7 Triglycerides: Is it a Risk Factor or a Risk Marker for Atherosclerosis and Cardiovascular Disease ? The Impact of Genetic Mutations on (ANGPTL4) Gene, encoder of (angiopoietin-like 4) Protein, inhibitor of Lipoprotein Lipase

Triglyceride levels rise from excess carbohydrate intake. They correlate with elevated bad cholesterol (LDL). In my own PhD Dissertation research, they also modify the temperature at which the liquid crystals of cholesterol shift from liquid to solid (from above to below normal body temperature) and hence may play a key role in unstable plaque and endothelial injury. The following curation looks at other aspects of triglycerides, while pointing to the generally important distinction between risk factor by association versus causation.

Reporters, Curators and Authors: Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/03/13/triglycerides-is-it-a-risk-factor-or-a-risk-marker-for-atherosclerosis-and-cardiovascular-disease-the-impact-of-genetic-mutations-on-angptl4-gene-encoder-of-angiopoietin-like-4-protein-that-in/

 

5.8 HDL – Is the Higher the Better or is it the HDL/LDL Ratio that matters even more?

5.8.1 HDL-C: Target of Therapy – Steven E. Nissen, MD, MACC, Cleveland Clinic vs Peter Libby, MD, BWH

Although bad cholesterol (LDL) is the focus of treatment and risk reduction for patients with stroke, heart attack or high risks for those, good cholesterol (HDL), which plays a role in clean up (LDL=trash, HDL=trash cans) is not always good, and may change character at menopause. Treatment for low HDL is currently limited in practice to exercise, 1-2 portions of alcohol per day if well tolerated, and choosing a statin that doesn’t lower HDL too much while lowering LDL.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/11/07/hdl-c-target-of-therapy-steven-e-nissen-md-macc-cleveland-clinic-vs-peter-libby-md-bwh/

 

5.8.2 Risk of Major Cardiovascular Events by LDL-Cholesterol Level (mg/dL): Among those treated with high-dose statin therapy, more than 40% of patients failed to achieve an LDL-cholesterol target of less than 70 mg/dL.

Meta analysis (combining data from multiple studies) shows that LDL of 40 (strong clean up mode) is better than 70 (moderate clean up mode) which is better than 100 (break even), 130 (mild cholesterol/blockage build up rate), or 160+ (strong disease build up). However, many patients on statins do not achieve even the modest goal of LDL<70 which is recommended for anyone with diabetes or with consequences from arterial blockages.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/07/29/risk-of-major-cardiovascular-events-by-ldl-cholesterol-level-mgdl-among-those-treated-with-high-dose-statin-therapy-more-than-40-of-patients-failed-to-achieve-an-ldl-cholesterol-target-of-less-th/

 

5.8.3 Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

What is the best way to identify blood clot vs bleed risk due to the status of coagulation factors?  PT, PTT, ACT, fibrinogen levels, factor VII, factor VIII, factor IX, von Willebrand factor?. The following curation looks at the formulation of a consensus among experts.

Curators: Larry H. Bernstein and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/11/28/special-considerations-in-blood-lipoproteins-viscosity-assessment-and-treatment/

 

5.9 Cholesteryl Ester Transfer Protein (CETP) Inhibitor: Potential of Anacetrapib to treat Atherosclerosis and CAD

The Reverse Cholesterol Transport (RCT) system is thought to play a major role in driving the removal of cholesterol mediated by the good cholesterol, HDL. A medication was developed to treat that, possibly most important for patients with low or ineffective HDL, but it was bundled with a statin, and limited by liver toxicity.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/04/07/cholesteryl-ester-transfer-protein-cetp-inhibitor-potential-of-anacetrapib-to-treat-atherosclerosis-and-cad/

 

5.10 Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore

Pharma places its money in technologies they hope will lead to high winnings. This curation discusses CEO decisions on where to invest, including consideration of biologic agents to boost reverse cholesterol transport by supporting the role of LCAT.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/04/03/fight-against-atherosclerotic-cardiovascular-disease-a-biologics-not-a-small-molecule-recombinant-human-lecithin-cholesterol-acyltransferase-rhlcat-attracted-astrazeneca-to-acquire-alphacore/

5.11 Boston Heart Diagnostics (BHD) offers Statin Induced Myopathy (SLCO1B1) Genotype test and genetic tests targeting ApoE, Factor V Leiden, prothrombin (Factor II), and CYP2C19

Genetic testing may help avoid problems by scouting which patients have elevated risk for complications, such as the one-in-a-million severe muscle damage from a statin. This issue is confounded by the commonness of muscle aches from statin-induced coQ10 deficiency that is easily remedied by taking coQ10 100 mg daily. Boston Heart Diagnostics garnered approval for a genetic test to check for risk of serious myopathy on a statin (prior to taking one).

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/17/boston-heart-diagnostics-bhd-offers-statin-induced-myopathy-slco1b1-genotype-test-and-genetic-tests-targeting-apoe-factor-v-leiden-prothrombin-factor-ii-and-cyp2c19/

 

5.12 The Role of Sibling Kinship, Sex, and Age of Ischemic Stroke Onset: The Familial Component

Cheaper than genetic testing, tracking family histories has identified a 60% increased risk for ischemic stroke in individuals having a sibling with prior stroke (and gender of either sibling was not a factor). 

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/30/the-role-of-sibling-kinship-sex-and-age-of-ischemic-stroke-onset-the-familial-component/

 

5.13 Genomics of Incident Ischemic Stroke Events, Stroke and Cardiovascular Disease

Transition from family history to specific genes and gene products offers a pathway to treatment, but the results can be multifactorial and differ from family to family, so the path to discovery of a generalizable treatment can be difficult.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/30/genomics-of-incident-ischemic-stroke-events-stroke-and-cardiovascular-disease/

 

Chapter 6

Epigenetics, Gender differences and Life Style: DM, Obesity, Hormonal Markers, Diets, Chrono-therapeutics

6.1 2014 Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism Conference: San Francisco, Ca. Conference Dates: San Francisco, CA 3/18-21, 2014

This curation summarizes a conference on the American Heart Association Guide for Improving Cardiovascular Health at the Community Level.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/26/2014-epidemiology-and-prevention-nutrition-physical-activity-and-metabolism-conference-san-francisco-ca-conference-dates-san-francisco-ca-318-21-2014/

 

6.2 Higher BMI (Obesity Marker): Earlier onset of incident CVD followed by Shorter overall Survival – Men and women of all ages

A study on onset of cardiovascular disease shows obese patients only appear to survive longer after onset because they get the seminal event (such as heart attack) earlier, e.g., by  7 years; the net lifespan is shortened by obesity (clearing up a prior paradox of longer survival for obese patients after MI).

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/03/05/higher-bmi-obesity-marker-earlier-onset-of-incident-cvd-followed-by-shorter-overall-survival-men-and-women-of-all-ages/

 

6.3 SNP-based Study on high BMI exposure confirms CVD and DM Risks – no associations with Stroke

A genetic examination of the impact of obesity on cardiovascular and diabetes risks looked at 93 single-nucleotide polymorphisms associated with body mass (BMI) in prior genome-wide association studies. The meta analysis identified elevated risks (odds ratio=OR>1 ) for Hypertension (OR 1.64, 95% CI 1.48-1.83), Coronary heart disease (CHD; OR 1.35, 95% CI 1.09-1.69), Type 2 diabetes (OR 2.53, 95% CI 2.04-3.13), Systolic blood pressure (β 1.65 mm Hg, 95% CI 0.78-2.52 mm Hg and Diastolic blood pressure (β 1.37 mm Hg, 95% CI 0.88-1.85 mm Hg).

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/07/10/snp-based-study-on-high-bmi-exposure-confirms-cvd-and-dm-risks-no-associations-with-stroke/

 

6.4 Coronary Heart Disease Research: Sugar Industry influenced national conversation on heart disease – Adoption of Low Fat Diet vs Low Carbohydrates Diet

The initial government recommended Dietary Goals for Americans (1977) proposed increases in carbohydrate intake and decreases in fat, saturated fat, cholesterol, and salt consumption but evidence was lacking and may have been influenced by lobbyists such as sugar producers.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/09/17/coronary-heart-disease-research-sugar-industry-influenced-national-conversation-on-heart-disease-adoption-of-low-fat-diet-vs-low-carbohydrates-diet/

 

6.5 Resveratrol, an antioxidant found in red wine presented since 2003 for its potential to lower risk for cardiovascular disease and neurodegeneration by increasing cell survival and slowing aging: 2014 Study – Diet rich in resveratrol offers no health boost

Oxidation of bad cholesterol (LDL) markedly increases its uptake into arterial walls, so antioxidants such as vitamin E and Resveratrol, an antioxidant found in red wine, have been recommended, but studies do NOT show benefit.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/07/25/resveratrol-an-antioxidant-found-in-red-wine-2014-study-resveratrol-offers-no-health-boost/

 

6.6 Prolonged Wakefulness: Lack of Sufficient Duration of Sleep as a Risk Factor for Cardiovascular Diseases – Indications for Cardiovascular Chrono-therapeutics

Data collated from multiple sources suggest that  the restorative function of sleep may be a consequence of nocturnal removal of potentially neurotoxic waste products. Impaired sleep, and in particular sleep apnea, is established as a “silent killer” that promotes arrhythmias, and has associations with obesity, hypertension, atherosclerosis, stroke, heart failure, cardiac arrhythmias, sudden death, and the metabolic syndrome.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/02/prolonged-wakefulness-lack-of-sufficient-duration-of-sleep-as-a-risk-factor-for-cardiovascular-diseases-indications-for-cardiovascular-chrono-therapeutics/

 

6.7 Testosterone Therapy for Idiopathic Hypogonadotrophic Hypogonadism has Beneficial and Deleterious Effects on Cardiovascular Risk Factors

Testosterone supplements may counteract symptoms from low levels, and may boost muscle mass and combat obesity, but the risk of having a nonfatal heart attack more than doubled for men age 65 or older during the three months after starting a testosterone prescription. Sometimes there may be other factors such as low growth hormone, vasculitis (high sed rate or CRP or abnormal ANCA) or low thyroid function that are safer to treat.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/30/testosterone-therapy-for-idiopathic-hypogonadotrophic-hypogonadism-has-beneficial-and-deleterious-effects-on-cardiovascular-risk-factors/

 

6.8 2014 Winter in New England: The Effect of Record Cold Temperatures on Cardiovascular Diseases

Hazards from cold weather, and tips to mitigate the risks, are presented in an easy to follow survey of relevant aspects.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/21/2014-winter-in-new-england-the-effect-of-record-cold-temperatures-on-cardiovascular-diseases/

 

6.9 Is it Hypertension or Physical Inactivity: Cardiovascular Risk and Mortality – New results in 3/2013

A study in Australia of population attributable risk (PAR) for heart disease claims after age 30, inactivity tops the risk factor list of high body mass index (BMI), smoking, high blood pressure (BP) and physical inactivity.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/19/is-it-hypertension-or-physical-inactivity-cardiovascular-risk-and-mortality-new-results-in-32013/

 

6.10 Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes

The examination of genes and gene products continues to clarify how our bodies function and where to seek new opportunities for beneficial diagnostics and treatments. The following curation presents information gleaned about peroxisome proliferator-activated receptors (PPARs) which play essential roles in the regulation of cellular differentiation, development, metabolism (carbohydrate, lipid, protein), and tumorigenesis.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/11/13/peroxisome-proliferator-activated-receptor-ppar-gamma-receptors-activation-pparγ-transrepression-for-angiogenesis-in-cardiovascular-disease-and-pparγ-transactivation-for-treatment-of-dia/

 

6.11 Sex and Gender Connections: Heart and Brain Disease in Women

The National Institutes of Health has made Sex (gender) a Biological Variable (SABV) key to all research it funds, in order to promote clarity on gender differences, rather than assume prior male-dominated research subjects adequately represent women too.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/28/sex-and-gender-connections-heart-and-brain-disease-in-women/

 

6.12 Females and Non-Atherosclerotic Plaque: Spontaneous Coronary Artery Dissection – New Insights from Research and DNA Ongoing Study

A video from the Mayo Clinic Grand Rounds features cardiologists Rajiv Gulati MD PhD and Sharonne Hayes MD discussing “Spontaneous Coronary Artery Dissection: New Insights and New Questions About This-Not-So-Rare Condition” which is more common among women than men.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/12/female-and-non-atherosclerotic-plaque-spontaneous-coronary-artery-dissection-new-insights-from-research-and-dna-ongoing-study/

 

Chapter 7

Blood Pressure Management:

Genetics & Human Adaptive Immunity in Hypertension

Hypertension (high blood pressure) stresses the heart and vessels, leading to thickening of the heart and vessels as well as damage to the lining (endothelium), elevation of the pressures needed to fill the heart, and eventually heart failure and other complications. Many patients resist control of blood pressure or have variations in pressure throughout the day so that a good blood pressure in the doctor’s office in the morning may not represent the daily risk of on-going damage. Often two or three different targets of therapy are warranted, customized to the cause and response. For patient convenience, multiple arms of treatment may be combined into a single pill, but it may be best to start with separate pills to optimize the dose of each, then see if that corresponds to a manufactured combination. The days of pharmacists making combinations for the individual are over.

 

7.1 Richard Lifton, MD, PhD of Yale University & Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prize Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

Richard Lifton was one of six scientists honored with $18 million in prizes at gala ceremonies hosted by actor Kevin Spacey. Lifton and his colleagues identified patients around the world with exceptionally high or low blood pressure due to single gene mutations and established their role in salt reabsorption by the kidney and regulation of blood pressure, which led to development of new therapies. 

The Six 2014 Life Scientists Laureates were: 

• James P. Allison (M. D. Anderson Cancer Center), for the discovery of T cell checkpoint blockade as effective cancer therapy.[7]
• Mahlon DeLong (Emory University), for defining the interlocking circuits in the brain that malfunction in Parkinson’s disease. This scientific foundation underlies the circuit-based treatment of Parkinson’s disease by deep brain stimulation.
• Michael N. Hall (Biozentrum University of Basel), for the discovery of Target of Rapamycin (TOR) and its role in cell growth control.
• Robert Langer (Massachusetts Institute of Technology), for discoveries leading to the development of controlled drug-release systems and new biomaterials.
• Richard P. Lifton (Yale University School of Medicine at Yale University), for the discovery of genes and biochemical mechanisms that cause hypertension.
• Alexander Varshavsky (California Institute of Technology), for discovering critical molecular determinants and biological functions of intracellular protein degradation.

SOURCE

https://breakthroughprize.org/News/6

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/03/03/richard-lifton-md-phd-of-yale-university-and-howard-hughes-medical-institute-recipient-of-2014-breakthrough-prizes-awarded-in-life-sciences-for-the-discovery-of-genes-and-biochemical-mechanisms-tha/

 

7.2 Sets of co-expressed Genes influence Blood Pressure Regulation: Genome-wide Association and mRNA expression @US National Heart, Lung, and Blood Institute

This curation surveys examples of different population statistic studies in relation to gene expression, co-expression and SNPs to examine how combined genome-wide association and mRNA expression data can clarify mechanisms of blood pressure regulation.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/04/16/sets-of-co-expressed-genes-influence-blood-pressure-regulation-genome-wide-association-and-mrna-expression-us-national-heart-lung-and-blood-institute/

 

7.3 Hypertension: It is Autoimmunity that Underlies its Development in Humans

This curation examines the role of the autoimmune system in blood pressure regulation.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/08/hypertension-it-is-autoimmunity-that-underlies-its-development-in-humans/

 

7.4 Pathophysiology in Hypertension: Opposing Roles of Human Adaptive Immunity

Drilling further into the linkage between the autoimmune system and vascular remodeling associated with blood pressure problems supports review of how T effector and regulatory lymphocytes, members of the adaptive immune system, play contrasting roles in hypertension.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/08/19/pathophysiology-in-hypertension-opposing-roles-of-human-adaptive-immunity/

 

7.5 2017 Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults – A Report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines

The American College of Cardiology and American Heart Association Task Force on Clinical Practice Guidelines garnered a consensus from teams of experts to provide guidelines for diagnosis and treatment, which have since shifted the definition of normal systolic blood pressure goal to 100-130 mmHg.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/11/14/2017-guideline-for-the-prevention-detection-evaluation-and-management-of-high-blood-pressure-in-adults-a-report-of-the-american-college-of-cardiology-american-heart-association-task-force-on-clin/

 

7.6 Hypertension – JNC 8 Guideline: Henry R. Black, MD, Michael A. Weber, MD and Raymond R. Townsend, MD

Members of expert teams discuss the process of forming a consensus opinion, including the role of liberal vs conservative slant.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/12/hypertension-jnc-8-guideline-henry-r-black-md-michael-a-weber-md-and-raymond-r-townsend-md/

 

7.7 What Level of Blood Pressure (BP) should be Treated? Comments on the New Guidelines

Further analysis of guidelines reveals potential influence of lobbyists and consulting relationships.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/01/24/what-level-of-blood-pressure-bp-should-be-treated-comments-on-the-new-guidelines/

 

7.8 2014 High Blood Pressure Research Conference, 9/9/2014 – 9/12/2014 — Hilton SF Union Square, San Francisco, CA

Announcements of AHA Conferences aim to connect cross-disciplinary researchers and clinicians from around the world; in preparation, current topics of interest are proposed. For a conference on hypertension in 2014, pre-selected topics included: Aldosterone, Its Receptors and Other Hormones, Angiotensin Action and Signaling, Angiotensin, ACE Renin and Prorenin, Blood Pressure Monitoring, Brain Mechanisms, Cardiac Hypertrophy and Dysfunction, Cardiovascular-Renal Interactions, Cerebrovascular Disease and Stroke, Chronic Kidney Disease, Diabetes, Endothelial Function and Aging, Epidemiology, Gender Differences, Genetics, Gene Therapy, Proteomics and Metabolomics, Inflammation, Immunity and Cytokines, Non-invasive Methods, Novel Therapeutic Approaches, Clinical Studies and Trials, Nutrition and Hypertension, Obesity Insulin Resistance and Metabolic Syndrome, Oxidative Stress, Peripheral Neural Mechanisms, Pregnancy and Preeclampsia, Receptors and Signal Transduction, Renal Hemodynamics and Renovascular Hypertension, Renal Nerves, Renal Tubular Transport, Renin-Angiotensin System, Salt and Hypertension, Secondary Resistant and Renovascular Hypertension, Vascular Biology, Vascular Remodeling and Dysfunction, and Vascular Stiffness.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/24/2014-high-blood-pressure-research-conference-99-912-2014-hilton-sf-union-square-san-francisco-ca/

 

7.9 Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management

Arterial stiffness can predict cardiovascular adverse events such as stroke and heart attack. We collated and comment on various approaches to that evaluation, including  the use of carotid-femoral pulse wave velocity (cfPWV), which has demonstration of clinical value even if office blood pressure and echo LV mass are normal (in which case, the problem would likely be missed in practices that do not check cfPWV).

Curators: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/24/imaging-biomarker-for-arterial-stiffness-pathways-in-pharmacotherapy-for-hypertension-and-hypercholesterolemia-management/

 

7.10 Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes

The  Seventh Report of the Joint National Committee on Prevention reviews collective experience in the management of high blood pressure and forms consensus expert opinions and recommendations, including the use of “triple” therapy (beta blocker, diuretic, ACEI/ARB/ARNI) for diabetics. Patients resistant to that may benefit from addition of an aldosterone inhibitor (e.g., spironolactone) and/or alpha blockers (e.g., clonidine) or minoxidil. Note that beta-blockers differ in fat solubility (impact on brain) and beta-1 selectivity (impact on airways). A fat soluble beta blocker such as nadolol calms tremor and migraines but may aggravate or cause depression. Higher beta-1 selectivity may resolve wheezing (selectivity factors: carvedilol 0.6, metoprolol 6, bisoprolol 20, bystolic 40). 

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/05/29/445/

 

7.11 Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH) – riociguat (Adempas, Bayer) for the treatment of Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH) – Approved by FDA 10/2013

Understanding treatment mechanisms, new drug approvals, and motivations can serve both as a guide to new solutions, and an awareness of new opportunities for patients not achieving goals. Here you can learn about approval of Riociguat for pulmonary hypertension, a vasodilator that restores the nitric-oxide–soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) pathway by directly stimulating sGC independent of NO and sensitizing sGC to low levels of NO. 

The World Health Organization (WHO) classifies pulmonary hypertension as I (intrinsic), II (CHF), III (lung disease), IV (CTEF=embolic), and/or V (drug or hereditory non-pulmonary e.g.telangiectasia, hemochromatosis, histo, platelet dysfunction, HIV, etc.). 

High risk (>10% 1-year mortality) is identified by clinical signs of right heart failure, rapid progression, repeated syncope, functional class IV, 6-minute walk (6MW) <165 m, B-type natriuretic peptide (BNP) 300 ng/L, pericardial effusion, right arterial pressure >14 mm Hg, cardiac index (CI) <2.0 L/m/m2, and mixed venous oxygen saturation (SvO2) <60%.

Low risk (<5% in 1-year mortality) is identified by no signs of right heart failure, no progression of symptoms, functional class I or II, 6MW >440 m, BNP <50 pg/L, no pericardial effusion, normal right atrial (RA) size, RA pressure <8 mm Hg, CI =2.5 L/min/m2, and SvO2 >65%.

PAH describes a group of PH patients (e.g., idiopathic, heritable, congenital heart, CTD, human immunodeficiency virus, portal hypertension, drugs, and toxins) who merit right heart catheterization (RHC) to characterize hemodynamically as precapillary PH, defined by a pulmonary artery wedge pressure (PAWP) =15 mm Hg and a pulmonary vascular resistance (PVR) >3 Wood units (WU) in the absence of other causes of precapillary PH such as due to hypoxemia/lung diseases, or chronic thromboembolism, versus Post-capillary PH related to left heart and valve disease which is defined as a PAWP >15 mm Hg with a diastolic pressure gradient (DPG = dPA – PCWP) <7 mm Hg and PVR =3 WU. Combined post- and precapillary PH is defined with PCWP >15 mm Hg with DPG =7 mm Hg and PVR >3 WU. 

Riociguat may help precapillary pulmonary hypertension, but may be harmful in post-capillary.

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/01/29/riociguat-adempas-bayer-for-the-treatment-of-chronic-thromboembolic-pulmonary-hypertension-cteph-and-pulmonary-arterial-hypertension-pah-approved-by-fda-102013/

Chapter 8

Anti-arrhythmic Drugs 

Atrial Fibrillation (AF) & Silent Cerebral Infarctions

Therapy Strategies: 

• Rate control for atrial fibrillation:

1. Drugs: Beta Blockers, diltiazem, verapamil, digoxin, amiodarone.
2. Surgical intervention: AV ablation
3. Medical Devices:  Pacemaker

• Rhythm control for atrial fibrillation: amiodarone, sotalol, ibutilide, flecainide, propafenone, pill-in-pocket

 

8.1 Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

An excellent review of the cardiac conduction system (the mechanisms for communication of the signals that trigger the heart beat and coordinate heart contraction by heartbeat impulse generation and propagation) serves as a stepping stone to analysis of genetic causes of problems that may cause fainting or sudden death. 

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/04/28/genetics-of-conduction-disease-atrioventricular-av-conduction-disease-block-gene-mutations-transcription-excitability-and-energy-homeostasis/

 

8.2 Effectiveness of Anti-arrhythmic Drugs: Amiodarone and Lidocaine, for treating sudden cardiac arrest, increasing likelihood of Patients Surviving Emergency Transport to Hospital

For patients who have conduction or rhythm problems, it is vital to know the effectiveness of anti-arrhythmic drugs, such as Amiodarone or Lidocaine, for treating sudden cardiac arrest. Used by emergency medical technicians (EMT), these can increase the likelihood of patients surviving emergency transport to a hospital. Amiodarone can take up to 6 hours to correct VFIB, so it has been responsible for some cases of Lazarus syndrome, rising from the dead, by late return of circulation after failed attempts at resuscitation – hence ventilation and circulation support should not be terminated prematurely in patients with sustained VFIB treated with amiodarone who may have a delayed recovery.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/04/04/effectiveness-of-anti-arrhythmic-drugs-amiodarone-and-lidocaine-for-treating-sudden-cardiac-arrest-increasing-likelihood-of-patients-surviving-emergency-transport-to-hospital/

 

8.3 Atrial Fibrillation and Silent Cerebral Infarctions: A Meta Analysis Study and Literature Review

Patients with AFib (or AFLUTTER) are at a 40% increased risk for developing cognitive impairment, and population studies offer an explanation: showers of small emboli cause sub-clinical strokes at twice the rate of patients without AFIB/AFLUTTER. It is generally understood to take 24 hours of AFIB or AFLUTTER to form blood clots (thrombi) and begin to cause brain injuries. Scoring systems such as CHA2DS2-vasc and HAS-BLED guide clinicians in the use of anticoagulants (e.g. apixaban vs coumadin) to offset that risk. Recent analysis of pacemaker and ICD device reports of heart rhythm suggest that patients may take the “tailored” approach of checking their rhythm once or twice daily to catch AFIB or AFLUTTER in time to prevent a 24 hour duration (PILL-IN-POCKET) and take an anticoagulant only when episodes endure despite anti-arrhythmia medications (e.g., Tikosyn, Sotalol, amiodarone) and cardioversions or ablation, if the risk of a bleeding complication is sufficiently low. Alternatively, they may get a WATCHMAN device implanted into the left atrial appendage.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/11/04/atrial-fibrillation-and-silent-cerebral-infarctions-a-meta-analysis-study-and-literature-review/

 

8.4 Sustained Cardiac Atrial Fibrillation: Management Strategies by Director of the Arrhythmia Service and Electrophysiology Lab at The Johns Hopkins Hospital

Dr. Hugh G. Calkins, M.D of Johns Hopkins Arrhythmia Center reports interesting facts about the harm of inadequately treated continual AFIB (or AFLUTTER), including: every second after a cerebral embolus from AFIB, 32,000 brain cells can die due to hypoxia from lack of blood flow, and in just 1 minute, nearly 2 million brain cells can die—increasing the risk of disability or death.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/16/sustained-cardiac-atrial-fibrillation-management-strategies-by-director-of-the-arrhythmia-service-and-electrophysiology-lab-at-the-johns-hopkins-hospital/

 

8.5 Cardiac Arrhythmias: A Risk for Extreme Performance Athletes

The downside of too much exercise:  this curation reviews how long-term training and competition in extreme endurance sports such as marathons, iron-man triathlons, competitive rowing and long-distance bicycle races may cause harmful structural changes to the heart and large arteries.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/08/cardiac-arrhythmias-a-risk-for-extreme-performance-athletes/

 

Chapter 9

MI, Acute Coronary Syndrome (ACS) and Heart Failure (HF)

Patients with heart failure have maladaptive responses from the kidneys, hoarding sodium and generating signals that stiffen the heart by activating fibrosis. Triple therapy for heart failure/avoidance of myocardial fibrosis mitigates that harm.

• ACEI
• Beta blocker combination
• Aldosterone Inhibitor

Aldosterone receptor antagonists (also called an antimineralocorticoid, MCRA, and sometimes MRA) are a class of drugs which block the effects of aldosterone. Aldosterone is the main mineralocorticoid hormone in the body and is produced in the adrenal cortex of the adrenal gland. Aldosterone increases sodium reabsorption by the kidneys, salivary glands, sweat glands and colon. At the same time, it increases the excretion of hydrogen and potassium ions.

By blocking the effects of aldosterone, aldosterone receptor antagonists block the reabsorption of sodium, which encourages water loss. Consequently, this leads to a decrease in blood pressure and a reduction in fluid around the heart.

Aldosterone receptor antagonists may be used in the treatment of high blood pressure or heart failure.

Common Aldosterone receptor antagonists Medications:

• spironolactone
• eplerenone

 

9.1 Acute Myocardial Infarction: Curations of Cardiovascular Original Research – A Bibliography

The following collection of references looks at methods for rapid diagnosis of heart attack, details of biologic changes, assessment of viability (potential gain from revascularization), therapies in addition to aspirin, nitrates, cautious short acting beta blockers, and decision for interventional catheterization (caution with beta blockers relates to TIMI trial evidence that in the first 24 hours of heart attack, an excess of longer acting beta blockers may cause death from cardiogenic shock). Other treatments include high dose statin for acute benefits, and additional anti-platelet medication that may interfere with bypass surgery.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/22/acute-myocardial-infarction-curations-of-cardiovascular-original-research-a-bibliography/

 

9.2 On-Hours vs Off-Hours: Presentation to ER with Acute Myocardial Infarction – Lower Survival Rate if Off-Hours

Prompt intervention in a catheterization laboratory saves lives and reduces damage for patients presenting within hours of an acute ST-elevation myocardial infarction or an infarction with a new left bundle branch block, but emergency care has its downside. Lesser injuries may be better managed medically until a well rested team without time pressure can carefully and methodically address the potential for benefits from revascularization (balloon angioplasty, stents, or bypass surgery).

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/22/on-hours-vs-off-hours-presentation-to-er-with-acute-myocardial-infarction-lower-survival-rate-if-off-hours/

 

9.3 Heart-Failure–Related Mortality Rate: CDC Reports comparison of 2000, 2012, 2014 – the decease is steadily reversed

The Center for Disease Control tracks outcomes which serve as a report card. The death toll from heart failure is slowly rising. Men have higher mortality than women, and blacks higher than whites. 

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/01/05/heart-failure-related-mortality-rate-cdc-reports-comparison-of-2000-2012-2014-the-decease-is-steadily-reversed/

 

9.4 Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?

A major part of mal-adaptive responses to heart failure may be summarized as a battle between kidneys and heart. When kidneys sense changes from heart failure, they make matters worse by hoarding sodium, promoting fibrosis and releasing endothelin, a peptide that constricts muscles in blood vessels, increasing blood pressure especially in the lungs. This curation discusses the three types of endothelin, the impact of phamcologic antagonsism (ambrisentan) on pulmonary artery hypertension, and the role of  measuring concentrations of big endothelin, endothelin-1 and other signals as noninvasive parameters for evaluation of disease. This curation reviews endothelin (a vasoconstrictor released by the kidney), and the endothelin antagonist Ambrisentan.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/19/clinical-trials-results-for-endothelin-system-pathophysiological-role-in-chronic-heart-failure-acute-coronary-syndromes-and-mi-marker-of-disease-severity-or-genetic-determination/

 

9.5 Amgen’s Corlanor® can help Reduce the Risk of Hospitalization for Patients with worsening Heart Failure

Amgen got FDA approval on April 15, 2015 for its drug Corlanor (ivrabradine) as an option to reduce need for hospitalization for patients with heart failure with EF <=35% who are in sinus rhythm >70 beats/min, with intolerance of increasing beta blockade. It is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that slows heart rate at the sinus node. It also can treat inappropriate sinus tachycardia (which can cause tachy-cardiomyopathy, a rate-related reversible cardiomyopathy) in patients intolerant of beta blockers.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/05/04/amgens-corlanor-can-help-reduce-the-risk-of-hospitalization-for-patients-with-worsening-heart-failure/

 

9.6 Heart Transplant (HT) Indication for Heart Failure (HF): Procedure Outcomes and Research on HF, HT @ Two Nation’s Leading HF & HT Centers

The American College of Cardiology (ACC) in conjunction with the American Heart Association (AHA) sponsors expert panel reports. This curation presents their recommendations regarding heart transplantation.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/07/09/research-programs-george-m-linda-h-kaufman-center-for-heart-failure-cleveland-clinic/

 

9.7 Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

The following curation addresses the roles of calcium channels in pulmonary arterial hypertension, including the biology of calcium and the actin skeleton, renal distal tubular Ca2+ exchange mechanism, calmodulin kinases, ryanodine receptors and the potential for an inhaler treatment for pulmonary arterial hypertension.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

 

9.8 Patients with Heart Failure & Left Ventricular Dysfunction: Life Expectancy Increased by coronary artery bypass graft (CABG) surgery: Medical Therapy alone and had Poor Outcomes

Patients with coronary disease and reduced ejection fraction and/or diabetes can have a net benefit both in lifespan and hospitalizations but undergoing the upfront risk of CABG surgery.

Curator: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2016/04/04/patients-with-heart-failure-left-ventricular-dysfunction-life-expectancy-increased-by-coronary-artery-bypass-graft-cabg-surgery/

 

9.9 Intravenous drug for the treatment of Acute Heart Failure (AHF) by Trevena, Inc. (Trevena) – Leader in the Discovery of G-protein coupled receptor (GPCR) biased ligands

This curation examines the business side of bearing fruit from genetic analysis of medical problems, resulting in a company based on a novel therapy, a beta-arrestin biased ligand of the angiotensin II type 1 receptor. The company focus is a clinical stage pharmaceutical corporation addressing G-protein coupled receptor (GPCR) biased ligands and their downstream effects.

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/10/10/intravenous-drug-for-the-treatment-of-acute-heart-failure-ahf-by-trevena-inc-trevena-leader-in-the-discovery-of-g-protein-coupled-receptor-gpcr-biased-ligands/

 

9.10 Treatment for Infective Endocarditis

For patients with a large valvular vegetation (>1 cm) associated with severe mitral or aortic regurgitation, without additional major surgical risks (age >80, hemmorhagic conversion risk of >5 cm brain injury, moderate-to-severe congestive heart failure, infective endocarditis complicated by heart block, annular or aortic abscess), early surgery can lower the risk of embolism from 21% to 0%.

Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2013/03/30/treatment-for-infective-endocarditis/

9.11 Preserved vs Reduced Ejection Fraction: Available and Needed Therapies

Description of circulatory problems has shifted from “forward and/or backward failure” to “systolic and/or diastolic failure,” and recently “heart failure with preserved or reduced ejection fraction.” Each has strengths and weaknesses, with the dominant issue that weak hearts draw the most attention, so word changes may help clinicians also address the underdog: backward failure, diastolic failure, stiff heart, which may cause heart failure even with preserved ejection fraction. The latest terminology is helpful in pointing out the seriousness of diastolic impairment as the cause of heart failure with preserved ejection fraction, but it falsely suggests it might be cured by a heart attack (if EF drops, it is no longer heart failure with preserved EF); the term heart failure with preserved EF fails to address the fact that diastolic stiffness can merit continued attention even if ejection fraction drops.  

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/02/03/preserved-vs-reduced-ejection-fraction-available-and-needed-therapies/

 

9.12 Publications on Heart Failure by Prof. William Gregory Stevenson, M.D., BWH

William Gregory Stevenson is a professor of medicine at HMS and Brigham and Women’s Hospital in Boston. He has an extensive bibliography regarding arrhythmia due to heart failure, and means to curtail the associated risk of death.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/13/publications-on-heart-failure-by-prof-william-gregory-stevenson-m-d-bwh/

 

Chapter 10

Calcium & Cardiovascular Diseases:

Contractile Dysfunction, Calcium as Neurotransmitter Sensor

Heart muscle function depends on a Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors. This reviews their roles in Cardiac Failure, Arterial Smooth Muscle, and Post-ischemic Arrhythmia.

 

Introduction

Archives of Medicine (AOM) to Publish from “Leaders in Pharmaceutical Business Intelligence (LPBI)” Open Access On-Line Scientific Journal http://pharmaceuticalintelligence.com

Reporter: Aviva Lev-Ari, PhD, RN

From our series on Calcium and Cardiovascular Diseases: A Series of Twelve Articles in Advanced Cardiology

AOM Editor-in-Chief’s Article Selection and Assignment of manuscript number: iMedPub Journals includes the following and is updated as soon as additional selections are made

 

Part I:

This is Part I in a series of articles on Calcium and Cell motility. Understanding the molecules and receptors expands opportunities for “biomarkers” (blood tests that report health status) as well as targets for therapy.

Identification of Biomarkers that are Related to the Actin Cytoskeleton 

Larry H Bernstein, MD, FCAP

  

Part II: 

This article is Part II in a series of articles on Calcium and its role in Cell motility. The topics addressed include:  Identification of Biomarkers that are related to the Actin Cytoskeleton, the Roles of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility, Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease, the Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets, Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter, Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure, Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy, Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism, Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor, Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission, and Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia.

iMedPub Journals-15-472

Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN

 

Part III:

Part III in the same series is the Third article of a multipart series covering Ca(2+) signaling and the cytoskeleton, with two on Ca2+ in cardiac contractility governed by the activations involving a ryanodine (RyR2) receptor and a specific calmodulin protein CaKIIδ with B and C splice variants.  In all of these discussions, Ca(2+) has a crucial role in many cellular events, not all of which are detailed, and its importance to cardiac function and function disorders is critical.   We shall next undertake the difficult examination of Ca(2+) movements in the kidney, which has a special relationship to vitamin D and bone mineral metabolism that is not of interest here. 

Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD
 and Aviva Lev-Ari, PhD, RN

Skeletal muscles are named for muscle bundles attached to skeleton elements, such as in the head and neck,  thorax, and the long bones of limbs, but the same structural and neuronally controlled muscle type is also in the abdomenal wall and the scalp, face, and eyes (for eye motion), each serving the function of movement on demand. The skeletal element these muscles attach to are tendons (fibrous tissue), often anchored to bone before and after an articulation (joint). There are several features that distinguish skeletal muscle from smooth muscle and from myocardium (heart muscle). Skeletal muscles are striated. They have fast-twitch and slow-twitch fibers in various proportions. They are under voluntary neural control, not autonomic (involuntary).

 

Part IV: 

has been been assigned the following manuscript number:

iMedPub Journals-15-471

The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, ArterialSmooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

 

Part V: 

has been been assigned the following manuscript number:

iMedPub Journals-15-516

Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

 

Part VI:

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

 

Part VII:

Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

  

Part VIII:

Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism – Part VIII

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

Part IX:

Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor – Part IX

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

Part X:

has been been assigned the following manuscript number:

iMedPub Journals-15-517

Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission – Part X

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

Part XI:

Sensors and Signaling in Oxidative Stress – Part XI

Larry H. Bernstein, MD, FCAP

 

Part XII:

Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD)) – Part XII

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

Part XIII:

has been been assigned the following manuscript number:

iMedPub Journals-15-471

Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

10.1 Calcium and Cardiovascular Diseases: A Series of Twelve Articles in Advanced Cardiology by Multiple Authors

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/28/calcium-and-cardiovascular-diseases-a-series-of-twelve-articles-in-advanced-cardiology/

 

10.2 Calcium-Channel Blocker, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

The signaling of smooth muscle cells by nerves occurs by calcium triggering neurotransmitter release by initiating synaptic vesicle fusion.   The mechanism by which this occurs is addressed in detail, and involves the interaction of soluble N-acetylmaleimide-sensitive factor (SNARE) and SM proteins, and in addition, the discovery of a calcium-dependsent Syt1 (C) domain of protein-kinase C isoenzyme, which binds to phospholipids.  The 2013 Lasker Prize was awarded to Richard Schell (Genentech) and Thomas Sudolf (Stanford University) for their discoveries concerning the molecular machinery and regulatory mechanism that underlie the rapid release of neurotransmitters, a process that underlies all of the brain’s activities. They identified and isolated many of this reaction’s key elements, unraveled central aspects of its fundamental mechanism, and deciphered how cells govern it with extreme precision.

Curators: Justin D. Pearlman, MD, PhD, FACC, Larry H. Bernstein, MD FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/16/calcium-channel-blocker-calcium-as-neurotransmitter-sensor-and-calcium-release-related-contractile-dysfunction-ryanopathy/

 

10.3 Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism

Calcium has a storage and release cycle that participates in the activation of muscle contraction for control not only of motion but also to control blood pressure and distribution. Homeostasis – the maintenance of status – requires controlled release of calcium from storage and return of calcium to storage. Such controls are critical both within cells, and for the entire biologic system. Thus the role of kidneys in maintaining the correct total body load of available calcium is just as vital as the sub-cellular systems of calcium handling in heart muscle and in the muscles that line arteries to control blood flow. The practical side to this knowledge includes not only identifying abnormalities at the cellular as well as system levels, but also identifying better opportunities to characterize disease and to intervene.

Curators: Larry H. Bernstein, MD FCAP, Justin D. Pearlman, MD, PhD, FACC, and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

 

10.4 Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

The mechanism of the signaling smooth muscle cells by parasympathetic nerves occurs by calcium triggering neurotransmitter release and synaptic vesicle fusion. It involves the interaction of soluble N-acetylmaleimide-sensitive factor (SNARE) and SM proteins, and in addition, a calcium-dependsent Syt1 (C) domain of protein-kinase C isoenzyme, which binds to phospholipids. 

Curators: Larry H. Bernstein, MD FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/

 

10.5 Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Catechols refer to the stress hormones that control our response to fright, flight and fight, e.g., epinephrine, also known as adrenaline. Sudden elevation of catechols increases heart rate and also the strength of heart contraction (contractility). In the short term, that provides a boost that supports special demands to run faster, work harder. Like the healthcare system, it is not sustainable in high gear. Excess catechol push causes heart failure (catechol toxicity). Race horses routinely develop pulmonary edema by the end of a race – those pretreated for that with the diuretic LASIX have an L next to their entry in the race ticket. The same issues occur as a whole-body system and at the sub-cellular level. Catechols increase amount and speed of the release of calcium which in turn triggers heart muscle contraction. However, the failing heart has elevated levels of calcium that impair oxygen utilization. The following discussions address the linkages between catechols and calcium traffic, including both the catechol and calcium stimulation of speed and strength, and their detrimental effects over time.

Curators: Justin D. Pearlman, MD, PhD, FACC, Larry H. Bernstein, MD FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-contractile/

 

10.6 Voltage-Gated Calcium Channel and Pharmacogenetic Association with Adverse Cardiovascular Outcomes: Hypertension Treatment with Verapamil SR (CCB) vs Atenolol (BB) or Trandolapril (ACE)

Single-nucleotide polymorphisms (SNPs) within the regulatory β2 subunit of the voltage-gated calcium channel (CACNB2) may contribute to variable treatment response to antihypertensive drugs and promote adverse cardiovascular outcomes. Atenolol has the undesirable distinction of not prolonging life like other beta blockers, possibly due to interfering with defenses against cancer.

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/01/02/voltage-gated-calcium-channel-and-pharmacogenetic-association-with-adverse-cardiovascular-outcomes-hypertension-treatment-with-verapamil-sr-ccb-vs-atenolol-bb-or-trandolapril-ace/

 

Chapter 11

Regeneration:

Cardiac System (cardiomyogenesis) and Vasculature (angiogenesis)

 

11.1 Regeneration: Cardiac System (cardiomyogenesis) and Vasculature (angiogenesis)

This curation reviews the fascinating abilities for cardiac regeneration addressed by Anthony Rosenzweig in Science 338, 1549 (2012)  – stem cell implants may help salvage a weak heart.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/15/regeneration-cardiac-system-and-vasculature

 

11.2 Gene, Meis1, Regulates the Heart’s Ability to Regenerate after Injuries.

In 2011, Dr. Sadek’s laboratory showed that the newborn mammalian heart is capable of a vigorous, regenerative response to injury through division of its own cells. As the newborn develops, the heart rapidly loses the ability to regenerate and to repair injuries such as heart attacks. The research team demonstrated that deletion of Meis1 gene (which turns off regeneration after birth) extended the proliferation period in the hearts of newborn mice, and also re-activated the regenerative process in the adult mouse heart without harmful effect on cardiac functions. 

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/03/gene-meis1-regulates-the-hearts-ability-to-regenerate-after-injuries/

 

11.3 Heart Renewal by pre-existing Cardiomyocytes: Source of New Heart Cell Growth Discovered


Some studies suggest stem cell activity provides differentiation of progenitors to cardiomyocytes, while other studies suggest that new cardiomyocytes are born at a very low rate, derived from the division of pre-existing cardiomyocytes. Pulse-chase genetic fate-mapping shows that the genesis of cardiomyocytes occurs at a low rate by the division of pre-existing cardiomyocytes during normal aging, a process that increases adjacent to areas of myocardial injury. 

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/23/heart-renewal-by-pre-existing-cardiomyocytes-source-of-new-heart-cell-growth-discovered/

 

11.4 Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral

This curation explores the role of Endothelial Progenitor Cells (cEPCs) in vessel growth and repair.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/29/positioning-a-therapeutic-concept-for-endogenous-augmentation-of-cepcs-therapeutic-indications-for-macrovascular-disease-coronary-cerebrovascular-and-peripheral/

 

11.5 Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs

As an extension of the 11.4, understanding the role of Endotherial Progenotor Cells is subject to careful definition and measurement – findings suggest that CD34/KDR is more appropriate for the definition of circulating EPC, whereas CFU (colony forming Unit) numbers may reflect their ability to proliferate. Fadini’s research supports the percentage of EPCs among the CD34+ pool vary widely from patient to patient and, in the same patient, under different pathophysiological conditions, indicating possible peripheral differentiation rather than bone-marrow mobilization.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/28/cardiovascular-outcomes-function-of-circulating-endothelial-progenitor-cells-cepcs-exploring-pharmaco-therapy-targeted-at-endogenous-augmentation-of-cepcs/

 

11.6 Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs

Further curation on Endotherial Progenotor Cells focuses on processes of injury reaction, mobilization, growth, differentiation, recruitment, homing, replication and migration.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/27/endothelial-dysfunction-diminished-availability-of-cepcs-increasing-cvd-risk-for-macrovascular-disease-therapeutic-potential-of-cepcs/

 

11.7 Macrovascular Disease – Therapeutic Potential of cEPCs: Reduction Methods for CV Risk

Literature explores the potential of circulating Endothelial Progenitor Cells (cEPCs) as a therapeutic target for pharmacological therapy design for cardiovascular risk reduction.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/07/02/macrovascular-disease-therapeutic-potential-of-cepcs-reduction-methods-for-cv-risk/

 

11.8 Bystolic’s generic Nebivolol – positive effect on circulating Endothelial Progenitor Cells endogenous augmentation

Pharmaceutical effects on eNOS, NO, and circulating Endothelial Progenitor Cells (cEPCs) make the information gleaned from genomics available for clinical applications.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/07/16/bystolics-generic-nebivolol-positive-effect-on-circulating-endothilial-progrnetor-cells-endogenous-augmentation/

 

 

Chapter 12

Vascular Biology, Atherosclerosis and Molecular Cardiology:

Vasculogenesis, Angiogenesis, and Arteriogenesis 

 

12.1 Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

Genome-wide stepwise regression analyses identified multiple independent associations from PLA2G7, CELSR2, APOB, KIF6, and APOE, reflecting the dependency of LpPLA2 on LDL-cholesterol levels. Most notably, several low frequency and rare coding variants in PLA2G7 were identified to be strongly associated with LpPLA2 activity: V279F (MAF=1.0%, P= 1.7e-108), a previously known association, and four novel associations due to I1317N (MAF=0.05%, P=4.9e-8), Q287X (MAF=0.05%, P=1.6e-7), T278M (MAF=0.02%, P=7.6e-5) and L389S (MAF=0.04%, P=4.3e-4). All these variants had enzyme activity lowering effects and each appeared to be specific to certain ethnicity. Comprehensive PGx analyses of baseline data provided insight into common and rare coding genetic variants associated with drug target and related traits valuable in facilitating future PGx investigation of darapladib response.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/17/synthetic-biology-on-advanced-genome-interpretation-for-gene-variants-and-pathways-what-is-the-genetic-base-of-atherosclerosis-and-loss-of-arterial-elasticity-with-aging/

 

12.2 Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use, Therapy Demand and Cost of Care

Inhaled nitric oxide has a checkered research history in part due to errors of case selection, timing and dosing, so although it offers life-saving therapy for some patients with acute lung disease, it is not widely used. Nitric oxide increases blood flow, and when inhaled, increases the flow specifically to regions that are well ventilated, which improves “ventilation-perfusion match” (relieving V/Q mismatch). When ventilation is regionally impaired, for example by a region of pneumonia, blood flowing through that region may not get its share of carbondioxide unloading and/or oxygen loading, leaving behind deoxygenated hypercarbic blood that may promote acidosis and possible death. Promoting a better match between blood flow and ventilation can improve the efficiency and alleviate a potentially life-threatening issue. 

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/03/clinical-indications-for-use-of-inhaled-nitric-oxide-ino-in-the-adult-patient-market-clinical-outcomes-after-use-therapy-demand-and-cost-of-care/

 

12.3 Inhaled Nitric Oxide in Adults: Clinical Trials and Meta Analysis Studies – Recent Findings

Observational studies of long-term use (>1 month) of continuous pulsed iNO (as monotherapy or as part of combination therapy) in a total of 14 patients with PAH across five studies reported improvement in high pressures with no significant adverse events, no elevated metHb levels, and no detectable exhaled or ambient NO or NO_2. 

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/02/inhaled-nitric-oxide-in-adults-with-acute-respiratory-distress-syndrome/

 

12.4 Prostacyclin and Nitric Oxide: Adventures in Vascular Biology – A Tale of Two Mediators

Professor S Moncada, at the Wolfson Institute for Biomedical Research, University College London, discusses his discovery of two substances, prostacyclin and nitric oxide, including the moments of insight and some of the critical experiments that contributed significantly to the uncovering of their roles in vascular biology.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/04/30/prostacyclin-and-nitric-oxide-adventures-in-vascular-biology-a-tale-of-two-mediators/

 

12.5 The Heart: Vasculature Protection – A Concept-based Pharmacological Therapy including THYMOSIN

Cardiogenesis requires the generation of endothelial, cardiac, and smooth muscle cells, thought to arise from distinct embryonic precursors. Genetic fate-mapping studies demonstrate that isl1^+ precursors from the second heart field can generate each of these diverse cardiovascular cell types in vivo.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/02/28/the-heart-vasculature-protection-a-concept-based-pharmacological-therapy-including-thymosin/

 

12.6 Resident-cell-based Therapy in Human Ischaemic Heart Disease: Evolution in the PROMISE of Thymosin beta4 for Cardiac Repair

Scientists at the Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, have demonstrated the ability to convert non-beating heart cells (which normally form scar tissue after a heart attack), into functional, beating heart muscle cells, by administering Thymosin beta 4 (Tβ4). Delivery of Tβ4, in conjunction with GMT (an acronym for three genes that normally guide embryonic heart development), resulted in reduction of scar area and improvement in cardiac function compared to GMT or Tβ4 alone. Within a month, non-beating cells that normally form scar tissue transformed into beating heart-muscle cells. Within three months, the hearts were beating even stronger and pumping more blood.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/04/30/93/

 

12.7 Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel

RegeneRx Biopharmaceuticals, Inc. is developing Tβ4 for the treatment of patients with acute myocardial infarction (AMI). The efforts include the formulation, development, and manufacture of a suitable drug product for use in the clinic, nonclinical pharmacology and toxicology studies, and the implementation of a phase 1 clinical protocol to assess the safety, tolerability, and the pharmacokinetics of Tβ4 in healthy volunteers. Tβ4 was shown to be expressed in the developing heart and found to stimulate migration of cardiomyocytes and endothelial cells, promote survival of cardiomyocytes and play an essential role in key stages of cardiac vessel development: vasculogenesis, angiogenesis, and arteriogenesis. 

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/02/27/arteriogenesis-and-cardiac-repair-two-biomaterials-injectable-thymosin-beta4-and-myocardial-matrix-hydrogel/

 

12.8 Thymosin References


Aviva Lev-Ari has compiled a list of references addressing thymosin in relation to cell therapy and tissue engineering.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/02/27/thymosin-references/

 

12.9 Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation

Endothelin receptors interact with eNOS and play a critical role in vascular tension, including coronary disease, renal disease, and erectile dysfunction. Intravenous administration of ET-1 causes a rapid decease in BP followed by a prolonged increase. The depressor response relates to PGI2 and NO release from the vascular endothelium. The pressor response is due to direct constriction of vascular smooth muscle. ETs exert direct positive inotropic and chronotropic actions on the heart and are potent coronary vasoconstrictors.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/04/endothelin-receptors-in-cardiovascular-diseases-the-role-of-enos-stimulation/

 

12.10 Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production

Phytoestrogens have received attention because of their potential for preventing some highly prevalent chronic diseases, including cardiovascular disease, osteoporosis, and hormone-related cancers. Genistein, the primary soy-derived phytoestrogen, has various biological actions including a weak estrogenic effect and inhibition of tyrosine kinases. Genistein acutely stimulates Nitric Oxide synthesis in vascular Eendothelial cells by a cyclic adenosine 5′-monophosphate-dependent mechanism, independent of PI3K/Akt or ERK/MAPK but depended on the cAMP/PKA cascade, not inhibited by an ER antagonist and unrelated to tyrosine kinase inhibition.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/07/19/cardiovascular-disease-cvd-and-the-role-of-agent-alternatives-in-endothelial-nitric-oxide-synthase-enos-activation-and-nitric-oxide-production/

 

12.11 Inhibition of ET-1, ETA and ETA-ETB, Induction of NO production, stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): cEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography

The curator has compiled a bibliography of references on inhibition of ET-1, ET_A and ET_A-ET_B, induction of NO production, stimulation of eNOS and treatment with PPAR-gamma agonists (TZD).

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/04/inhibition-of-et-1-eta-and-eta-etb-induction-of-no-production-and-stimulation-of-enos-and-treatment-regime-with-ppar-gamma-agonists-tzd-cepcs-endogenous-augmentation-for-cardiovascular-risk-reduc/

 

12.12 Vascular Medicine and Biology: Classification of Fast Acting Therapy for Patients at High Risk for Macrovascular Events – Macrovascular Disease – Therapeutic Potential of cEPCs

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/24/vascular-medicine-and-biology-classification-of-fast-acting-therapy-for-patients-at-high-risk-for-macrovascular-events-macrovascular-disease-therapeutic-potential-of-cepcs/

 

12.13 Mitochondria Dysfunction and Cardiovascular Disease – Mitochondria: More than just the “powerhouse of the cell”

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

 

Chapter 13

PharmacoGenomics for Cardiovascular Disease

 

 

13.1 Introduction to Genomics and Epigenomics Roles in Cardiovascular Diseases

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/01/05/introduction-to-genomics-and-epigenomics-roles-in-cardiovascular-diseases/

 

13.2 Genomics and Medicine: The Physician’s View

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/01/03/genomics-and-medicine-the-physicians-view/

 

13.3 Pharmacogenomics

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/01/31/pharmacogenomics/

 

13.4 Helping Physicians identify Gene-Drug Interactions for Treatment Decisions: New ‘CLIPMERGE’ program – Personalized Medicine @The Mount Sinai Medical Center

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/04/15/helping-physicians-identify-gene-drug-interactions-for-treatment-decisions-new-clipmerge-program-personalized-medicine-the-mount-sinai-medical-center/

 

13.5 Is Pharmacogenetic-based Dosing of Warfarin Superior for Anticoagulation Control?

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/02/04/is-pharmacogenetic-based-dosing-of-warfarin-superior-for-anticoagulation-control/

 

13.6 Summary of Genomics and Medicine: Role in Cardiovascular Diseases

Author: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/01/06/summary-of-genomics-and-medicine-role-in-cardiovascular-diseases/

 

Chapter 14

Drug Adverse Effects and Toxicity

 

 

14.1 Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects

Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/04/11/cardiotoxicity-and-cardiomyopathy-related-to-drugs-adverse-effects/

 

14.2 Amyloidosis with Cardiomyopathy

Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2013/03/31/amyloidosis-with-cardiomyopathy/

 

Summary to Part One

by Justin D. Pearlman, MD, PhD, FACC

Chapter 1 of Part One addressed current priorities based on prevalence, cost and burden. Hypertension and heart failure dominate the near future. Chapter 2 reviewed the types of pharmaceutical therapies, ranging from natural biochemicals and analogs to antibody mediated biologics and biosimilars. Chapter 3 focused on inflammation, which promotes heart attacks, strokes, and renal failure, as well as valve disease, cardiomyopathy and vasculitis. One group reported >30% reduction in heart attacks by correcting the inflammation marker hs-CRP with a biologic anti-inflammatory agent, while those using over-the-counter anti-inflammatory agents daily long term such as ibuprofen suffer an increase atherosclerotic blockages, heart attacks and strokes. Chapter 4 focused on blood clots, which cause pulmonary emboli, pulmonary hypertension, peripheral emboli and strokes. The NOAC apixaban (Eliquis) has documented that it is both more effective and safer as a “blood thinner” than coumadin, in addition to removing restriction on dietary greens, decreased interactions and obviating frequent blood tests, but it has not been tested or approved for mechanical heart valves. Paradoxically, the INR test required frequently to monitor coumadin dosing has random results for patients on apixaban, so it is not only not needed, it is misleading. Chapter 5 addresses cholesterol and atherosclerosis, the common cause of most heart attacks, strokes, peripheral artery disease and many cases of renal failure. Repatha and Praluent are biologics which offer marked improvements in the cholesterol profile, both for people who could not tolerate any of the statins, and for those not to goal on maximal tolerated statins. The LDL goal has been shifting lower, with evidence for better outcomes at 40 than 70 which is better than the break even level of 100 mg/dL, yet cost-effective concerns still have target at 70 just for symptomatic patients (diabetes, coronary disease or  TIAs), else 100-130 is still broadly accepted even though >100 promotes disease. Chapter 6 addressed influence of gender and lifestyle. Chapter 7 drilled down on hypertension control. Chapter 8 addressed pharmaceutics of heart rhythm control. Chapter 9 reviewed state-of-the-art for coronary artery disease management, which includes cholesterol management, beta-blockade versus rate-modifying calcium channel blockade (the two together can promote complete heart block and death as an interaction), nitrates, and the diastolic sodium channel blocker Ranexa, with growing evidence for consideration of anti-inflammatory biologics. Chapter 10 addressed pathways of calcium signaling. Chapter 11 discussed tissue regeneration (angiogenesis, stem cell therapy, and heart cell regeneration). Chapter 12 delved into vascular biology. Chapter 13 examined what genomics portends for the future of individualized cardiovascular medication. Chapter 14 examined adverse effects of pharmaco-therapies.

Part Two

Biomarkers as Determinants in Therapeutics Selection and as Diagnostics

 

Introduction by Justin D. Pearlman, MD, PhD, FACC  

Chapter 15: The Role of Biomarkers in Pharmaco-Therapy – Breakthroughs in BIOMARKER Development for Cardiovascular Disease

Chapter 16: Genomics Harnessed for Disease Diagnosis

Chapter 17: Biomarkers by Medical Indication and Diagnosis

Chapter 18: Emergent Cardiac Events – The Role of Biomarkers in Treatment

Chapter 19: Biomarkers for Assessment of Lipidemia, the role of Diet and Supplements

Chapter 20: Biomarkers for Inflammation Detection

Summary by Justin D. Pearlman, MD, PhD, FACC  

 

Introduction to Part Two

by Justin D. Pearlman, MD, PhD, FACC

Part Two examines the use of biochemicals as markers of disease status. A well known early example was testing for “cardiac enzymes” in the blood to identify a heart attack in progress, with CK-MB rise diagnostic but late (2-24 hours), largely supplanted by the biomarker troponin (not an enzyme) which rises earlier (1-2 hours), and is more sensitive and more specific if it rises to an elevated level sustained >6 days. However, it is not without controversy, as patients with hypertension or impaired renal function or cross-reacting antibodies show elevations that many physicians label as heart attack instead of the more proper less presumptuous label of “abnormal troponin level” and there are many instances of abnormal troponin level where echo shows no wall motion impairment and coronary angiography shows no blockages. The complete mapping of the human genome has laid the foundation for tremendous expansion of the number and use of biomarkers to clarify the status of cardiovascular and other disease processes.

Chapter 15

The Role of Biomarkers in Pharmacotherapy – Breakthroughs in Biomarker Development for Cardiovascular Disease

 

15.1 Clinical Biomarkers Overview

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/05/02/clinical-biomarkers-overview/

 

15.2 Biomarker Guided Therapy

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/02/01/biomarker-guided-therapy/

 

15.3 A Future for Plasma Metabolomics in Cardiovascular Disease Assessment

Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/09/09/a-future-for-plasma- -in-cardiovascular-disease-assessment/

 

15.4 Metabolomics based biomarker discoveries

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

https://pharmaceuticalintelligence.com/2013/07/09/metabolomics-based-biomarker-discoveries/

 

15.5 Assessing Cardiovascular Disease with Biomarkers – A Changing expectation from cardiac biomarkers.

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/12/25/assessing-cardiovascular-disease-with-biomarkers/

 

15.6 Diagnostic Value of Cardiac Biomarkers

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/01/04/diagnostic-value-of-cardiac-biomarkers/

 

15.7 Landscape of Cardiac Biomarkers for Improved Clinical Utilization

Curator and Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/09/22/landscape-of-cardiac-biomarkers-for-improved-clinical-utilization/

 

15.8 The Union of Biomarkers and Drug Development

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/12/24/the-union-of-biomarkers-and-drug-development/

 

15.9 Biomarkers: Diagnosis and Management, Present and Future

Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/11/10/biomarkers-diagnosis-and-management/

15.10 Personalized Medicine – The California Initiative

Curator: Demet Sag, PhD, CRA, GCP

https://pharmaceuticalintelligence.com/2015/10/12/personalized-medicine/

Chapter 16

Genomics Harnessed for Disease Diagnosis

 

16.1 Cardiology, Genomics and Individualized Heart Care

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/01/cardiology-genomics-and-individualized-heart-care-framingham-heart-study-65-y-o-study-jackson-heart-study-15-y-o-study/

 

16.2 Commentary on Biomarkers for Genetics and Genomics of Cardiovascular Disease: Views by Larry H Bernstein, MD, FCAP

Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/16/commentary-on-biomarkers-for-genetics-and-genomics-of-cardiovascular-disease-views-by-larry-h-bernstein-md-fcap/

 

16.3 Advances in Separations Technology for the “OMICs” and Clarification of Therapeutic Targets

Curator, Reporter, EAW: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/10/22/advances-in-separations-technology-for-the-omics-and-clarification-of-therapeutic-targets/

 

16.4 Platelet Endothelial Aggregation Receptor-1 (PEAR1) Gene to be most strongly associated with Dual Antiplatelet Therapy Response: Genetic Determinants of Variable Response to Aspirin (alone and in combination with Clopidogrel)

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/30/platelet-endothelial-aggregation-receptor-1-pear1-gene-to-be-most-strongly-associated-with-dual-antiplatelet-therapy-response-genetic-determinants-of-variable-response-to-aspirin-alone-and-in-comb/

 

16.5 Statin-Induced Low-Density Lipoprotein Cholesterol Reduction: Genetic Determinants in the Response to Rosuvastatin

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/02/statin-induced-low-density-lipoprotein-cholesterol-reduction-genetic-determinants-in-the-response-to-rosuvastatin/

 

16.6 Response to Rosuvastatin in Patients With Acute Myocardial Infarction: Hepatic Metabolism and Transporter Gene Variants Effect

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/01/02/response-to-rosuvastatin-in-patients-with-acute-myocardial-infarction-hepatic-metabolism-and-transporter-gene-variants-effect/

 

16.7 Congestive Heart Failure & Personalized Medicine: Two-gene Test predicts response to Beta Blocker Bucindolol

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/17/chronic-heart-failure-personalized-medicine-two-gene-test-predicts-response-to-beta-blocker-bucindolol/

 

16.8 Introduction to Genomics and Epigenomics Roles in Cardiovascular Diseases

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/01/05/introduction-to-genomics-and-epigenomics-roles-in-cardiovascular-diseases/

 

16.9 Precision Medicine for Future of Genomics Medicine is The New Era

Demet Sag, PhD, CRA, GCP

https://pharmaceuticalintelligence.com/2015/04/15/precision-medicine/

Chapter 17

Biomarkers by Medical Indication and Diagnosis

 

17.1: Hypertension

 

17.1.1 A Concise Review of Cardiovascular Biomarkers of Hypertension

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/04/25/a-concise-review-of-cardiovascular-biomarkers-of-hypertension/

 

17.1.2 What Level of Blood Pressure (BP) should be Treated? Comments on the New Guidelines

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/01/24/what-level-of-blood-pressure-bp-should-be-treated-comments-on-the-new-guidelines/

 

17.1.3 Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling

Author and Curator: Larry H Bernstein, MD, FCAP, Author and Cardiovascular Three-volume Series, Editor: Justin Pearlman, MD, PhD, FACC, and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/09/heart-smooth-muscle-excitation-contraction-coupling-ecc-cytoskeleton-cellular-dynamics-and-ca2-signaling/

 

17.1.4 FDA Adds Cardiac Drugs to Watch List – TOPROL-XL®

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/26/fda-adds-antinausea-cardiac-drugs-to-watch-list-medscape/

 

17.1.5 Blood Pressure Response to Antihypertensives: Hypertension Susceptibility Loci Study

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/01/02/blood-pressure-response-to-antihypertensives-atenolol-and-hydrochlorothiazide-hypertension-susceptibility-loci-study/

17.2 Atrial Fibrillation

 

17.2.1 Genetic Analysis of Atrial Fibrillation

Author and Curator: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev- Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/10/27/genetic-analysis-of-atrial-fibrillation/

 

17.2.2 Oxidized Calcium Calmodulin Kinase and Atrial Fibrillation

Author: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/10/26/oxidized-calcium-calmodulin-kinase-and-atrial-fibrillation/

 

17.2.3 Renal Function Biomarker, β-trace protein (BTP) as a Novel Biomarker for Cardiac Risk Diagnosis in Patients with Atrial Fibrilation

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/11/13/renal-function-biomarker-%CE%B2-trace-protein-btp-as-a-novel-biomarker-for-cardiac-risk-diagnosis-in-patients-with-atrial-fibrilation/

17.3 Atherosclerosis

 

17.3.1 Endothelial Function and Cardiovascular Disease

Pathologist and Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/10/25/endothelial-function-and-cardiovascular-disease/

 

17.3.2 Atherosclerosis: What is New in Biomarker Discovery

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/07/01/atherosclerosis-what-is-new-in-biomarker-discovery/

17.3.3 Two Classes of Antithrombotic Drugs: Anticoagulants and Antiplatelet drugs

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/06/25/two-classes-of-antithrombotic-drugs-anticoagulants-and-antiplatelet-drugs/

17.3.4 The Final Considerations of the Role of Platelets and Platelet Endothelial Reactions in Atherosclerosis and Novel Treatments

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/10/15/the-final-considerations-of-the-role-of-platelets-and-platelet-endothelial-reactions-in-atherosclerosis-and-novel-treatments/

17.3.5 CT Angiography & TrueVision™ Metabolomics (Genomic Phenotyping) for new Therapeutic Targets to Atherosclerosis

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/11/15/ct-angiography-truevision-metabolomics-genomic-phenotyping-for-new-therapeutic-targets-to-atherosclerosis/

 

17.3.6 Triggering of Plaque Disruption and Arterial Thrombosis

Curator and Reporter: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/10/13/triggering-of-plaque-disruption-and-arterial-thrombosis/

 

17.3.7 Biomarkers and risk factors for cardiovascular events, endothelial dysfunction, and thromboembolic complications

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/09/09/biomarkers-and-risk-factors-for-cardiovascular-events-endothelial-dysfunction-and-thromboembolic-complications/

 

17.3.8 Action of Hormones on the Circulation

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/02/17/action-of-hormones-on-the-circulation/

 

17.3.9 Endothelial Dysfunction (release into the circulation of damaged endothelial cells) as A Risk Marker for Ischemia and MI

Reporter and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/01/12/endothelial-dysfunction-as-risk-marker/

 

17.3.10 Circulating Endothelial Progenitors Cells (cEPCs) as Biomarkers

Article Curator: Larry H. Bernstein, MD, FCAP and Topic Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/14/circulating-endothelial-progenitors-cells-as-biomarkers/

 

17.3.11 Age-Dependent Depression in Circulating Endothelial Progenitor Cells in Coronary Artery Bypass Grafting Patients

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

https://pharmaceuticalintelligence.com/2012/08/17/age-dependent-depression-in-circulating-endothelial-progenitor-cells-in-coronary-artery-bypass-grafting-patients/

 

17.3.12 Cardiovascular Biology  – A Bibliography of Research @Technion

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/05/27/cardiovascular-biology-a-bibliography-of-research-technion/

 

17.4 Chronic Heart Failure

 

17.4.1 The Cardiorenal Syndrome in Heart Failure: Cardiac? Renal? syndrome?

Writer and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/30/the-cardiorenal-syndrome-in-heart-failure/

 

17.4.2 The role of biomarkers in the diagnosis of sepsis and patient management

Author: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/07/28/the-role-of-biomarkers-in-the-diagnosis-of-sepsis-and-patient-management/

 

17.4.3 Cardiovascular Complications: Death from Reoperative Sternotomy after prior CABG, MVR, AVR, or Radiation; Complications of PCI; Sepsis from Cardiovascular Interventions

Author, Introduction and Summary: Justin D Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/07/23/cardiovascular-complications-of-multiple-etiologies-repeat-sternotomy-post-cabg-or-avr-post-pci-pad-endoscopy-andor-resultant-of-systemic-sepsis/

 

17.4.4 Advanced Topics in Sepsis and the Cardiovascular System at its End Stage

Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-sepsis-and-the-cardiovascular-system-at-its-end-stage/

 

17.4.5 Heart Failure Treatment Improves, But Death Rate Remains High: NPR

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/29/heart-failure-treatment-improves-but-death-rate-remains-high-npr/

 

17.4.6 Erythropoietin (EPO) and Intravenous Iron (Fe) as Therapeutics for Anemia in Severe and Resistant CHF: The Elevated N-terminal proBNP Biomarker

Co-Author and Curator: Larry H. Bernstein, MD, FCAP and Article Architecture Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/10/epo-as-therapeutics-for-anemia-in-chf/

17.5 Diabetes

 

17.5.1 Comorbidity of Diabetes and Aging in Cardiovascular Diseases

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/11/comorbidity-of-diabetes-and-aging-in-cardiovascular-diseases/

17.5.2 Diabetes is caused by Leaky Calcium Channels in Pancreatic Beta Cells – research @Columbia University Medical Center: The Role of RyR2 in Regulation of Insulin Release and Glucose Homeostasis

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/04/14/diabetes-is-caused-by-leaky-calcium-channels-in-pancreatic-beta-cells-research-columbia-university-medical-center-the-role-of-ryr2-in-regulation-of-insulin-release-and-glucose-homeostasis/

 

17.5.3 Diabetes-risk Forecasts: Serum Calcium in Upper-Normal Range (>2.5 mmol/L) as a New Biomarker

Article Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/25/diabetes-risk-forecasts-serum-calcium-in-upper-normal-range-2-5-mmoll-as-a-new-biomarker/

17.6 Cancer Treatment Effect on Heart Disease

 

17.6.1 Cardio-oncology and Onco-Cardiology Programs: Treatments for Cancer Patients with a History of Cardiovascular Disease

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/08/cardio-oncology-and-onco-cardiology-programs-treatments-for-cancer-patients-with-a-history-of-cardiovascular-disease/

 

17.6.2 Radiation and Chemotherapy Therapy: The Pharmacological Risk for Developing Cardiovascular Disease

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/08/20316/

Chapter 18

Emergent Cardiac Events – The Role of Biomarkers in Treatment

18.1 Cause of Death: Heart Condition

 

18.1.1 Accurate Identification and Treatment of Emergent Cardiac Events

Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/03/15/accurate-identification-and-treatment-of-emergent-cardiac-events/

 

18.1.2 Myocardial Infarction: The New Definition After Re-vascularization

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/10/15/myocardial-infarction-the-new-definition-after-revascularization/

 

18.1.3 “Sudden Cardiac Death,” SudD is in Ferrer inCode’s Suite of Cardiovascular Genetic Tests to be Commercialized in the US

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/10/sudden-cardiac-death-sudd-is-in-ferrer-incodes-suite-of-cardiovascular-genetic-tests-to-be-commercialized-in-the-us/

 

18.2 Variants of Troponin in Measurement of Acute CVD Events

 

18.2.1 Troponin I in acute decompensated heart failure: insights from the ASCEND-HF study

Writer and Curator: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/30/troponin-i-in-acute-decompensated-heart-failure/

 

18.2.2 Dealing with the Use of the High Sensitivity Troponin (hs cTn) Assays: Preparing the United States for High-Sensitivity Cardiac Troponin Assays

Author and Curator: Larry H Bernstein, MD, FCAP, and Author and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/18/dealing-with-the-use-of-the-hs-ctn-assays/

 

18.2.3 More on the Performance of High Sensitivity Troponin T and with Amino Terminal Pro BNP in Diabetes

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/01/20/more-on-the-performance-of-high-sensitivity-troponin-t-and-with-amino-terminal-pro-bnp-in-diabetes/

 

18.2.4 Troponin T elevation has 20-fold increased ESRD rate

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/10/25/troponin-t-elevation-has-20-fold-increased-esrd-rate/

 

18.2.5 Identification of Biomarkers that are Related to the Actin Cytoskeleton

Curator and Writer: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/

 

18.2.6 Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI – Corus CAD, hs cTn, CCTA

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/

 

18.2.7 Novel Macromolecular IV to Oral Delivery Conversion Pathway: Anti-thrombolytic post-surgical – Catalent OptiGel Bio™ Technology

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/12/novel-macromolecular-iv-to-oral-delivery-conversion-pathway-anti-thrombolytic-post-surgical-catalent-optigel-bio-technology/

 

18.2.8 Hyperhomocysteinemia interaction with Protein C and Increased Thrombotic Risk

Reporter and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/12/03/hyperhomocysteinemia-interaction-with-protein-c-and-increased-thrombotic-risk/

Chapter 19

Biomarkers for Assessment of Dyslipidemia, the Role of Diet and Supplements

19.1 Cardio Protective Factors in Diet and Reduction of CVD Risk

 

19.1.1 Diet and Exercise

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/03/04/diet-and-exercise/

 

19.1.2 Lipid Metabolism

Reporter and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/15/lipid-metabolism/

 

19.1.3 Carbohydrate Metabolism

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/13/carbohydrate-metabolism/

 

19.1.4 Diet and Cholesterol

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/03/02/diet-and-cholesterol/

 

19.1.5 High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/03/31/high-density-lipoprotein-hdl-an-independent-predictor-of-endothelial-function-artherosclerosis-a-modulator-an-agonist-a-biomarker-for-cardiovascular-risk/

19.1.6 Leptin signaling in mediating the cardiac hypertrophy associated with obesity

Reviewers and Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/11/03/leptin-signaling-in-mediating-the-cardiac-hypertrophy-associated-with-obesity/

 

19.1.7 Importance of Omega-3 Fatty Acids in Reducing Cardiovascular Disease

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

https://pharmaceuticalintelligence.com/2013/04/29/importance-of-omega-3-fatty-acids-in-reducing-cardiovascular-disease/

 

19.1.8 Benefits of Fiber in Diet

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

https://pharmaceuticalintelligence.com/2018/03/14/benefits-of-fiber-in-diet/

 

19.1.9 Serum carotenoid concentrations and metabolic syndrome: interaction with smoking

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

https://pharmaceuticalintelligence.com/2013/05/27/serum-carotenoid-concentrations-and-metabolic-syndrome-interaction-with-smoking/

19.2 CVD and Hyperlipidemia

 

19.2.1 Voices from the Cleveland Clinic On Circulating apoA1: A Biomarker for a Proatherogenic Process in the Artery Wall

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/29/voices-from-the-cleveland-clinic-on-circulating-apoa1-a-biomarker-for-a-proatherogenic-process-in-the-artery-wall/

 

19.2.2 LDL, HDL, TG, ApoA1 and ApoB: Genetic Loci Associated With Plasma Concentration of these Biomarkers – A Genome-Wide Analysis With Replication

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/18/ldl-hdl-tg-apoa1-and-apob-genetic-loci-associated-with-plasma-concentration-of-these-biomarkers-a-genome-wide-analysis-with-replication/

 

19.2.3 Artherogenesis: Predictor of CVD – the Smaller and Denser LDL Particles

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/11/15/artherogenesis-predictor-of-cvd-the-smaller-and-denser-ldl-particles/

 

19.2.4 CVD Prevention and Evaluation of Cardiovascular Imaging Modalities: Coronary Calcium Score by CT Scan Screening to justify or not the Use of Statin

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/03/03/cvd-prevention-and-evaluation-of-cardiovascular-imaging-modalities-coronary-calcium-score-by-ct-scan-screening-to-justify-or-not-the-use-of-statin/

 

19.2.5 Hyper-triglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Under-treatment of High-Risk Cardiac Patients

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/04/04/hypertriglyceridemia-concurrent-hyperlipidemia-vertical-density-gradient-ultracentrifugation-a-better-test-to-prevent-undertreatment-of-high-risk-cardiac-patients/

19.3 Perspectives on the Role of Supplementation

 

19.3.1 Calcium (Ca) supplementation (>1400 mg/day): Higher Death Rates from all Causes and Cardiovascular Disease in Women

Curator: Aviva Lev-Ari, PhD. RN

https://pharmaceuticalintelligence.com/2013/02/19/calcium-ca-supplementation-1400-mgday-higher-death-rates-from-all-causes-and-cardiovascular-disease-in-women/

 

19.3.2 Supplements offer little CV benefit, and some are linked to harm

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/05/31/supplements-offer-little-cv-benefit-and-some-are-linked-to-harm-in-j-am-coll-cardiol/

 

19.3.3 Health benefit of anthocyanins from apples and berries noted for men

Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/06/health-benefit-of-anthocyanins-from-apples-and-berries-noted-for-men/

 

Chapter 20

Biomarkers for Inflammation Detection

 

20.1 Inflammation and Disease

 

20.1.1 Transcript Dynamics of Proinflammatory Genes

Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/03/04/transcript-dynamics-of-proinflammatory-genes/

 

20.1.2 Role of Inflammation in Disease

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/11/29/role-of-inflammation-in-disease/

 

20.1.3 What is the key method to harness Inflammation to close the doors for many complex diseases?

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/03/21/what-is-the-key-method-to-harness-inflammation-to-close-the-doors-for-many-complex-diseases/

 

20.1.4 New Insights into mtDNA, mitochondrial proteins, aging, and metabolic control

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/04/20/new-insights-into-mtdna-mitochondrial-proteins-aging-and-metabolic-control/

 

20.2 Inflammation dependent on Lipid level in CAD

 

20.2.1 A Second Look at the Transthyretin Nutrition Inflammatory Conundrum

Subtitle: Transthyretin and the Systemic Inflammatory Response

Author and Curator: Larry H. Bernstein, MD, FACP, Clinical Pathologist, Biochemist, and Transfusion Physician

https://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory-conundrum/

 

20.2.2 Reducing obesity-related inflammation

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/11/16/reducing-obesity-related-inflammation/

 

20.2.3 Importance of high sensitivity C-Reactive Protein (hs-CRP)

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/09/08/importance-of-high-sensitivity-c-reactive-protein-hs-crp/

 

20.2.4 Cardiovascular Risk: C-Reactive Protein BioMarker and Plasma Fibrinogen

Curator & Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/24/cardiovascular-risk-c-reactive-protein-biomarker-and-plasma-fibrinogen/

 

20.2.5 ODYSSEY Outcomes trial evaluating the effects of a PCSK9 inhibitor, alirocumab, on major cardiovascular events in patients with an acute coronary syndrome to be presented at the American College of Cardiology meeting on March 10, 2018.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/28/odyssey-outcomes-trial-evaluating-the-effects-of-a-pcsk9-inhibitor-alirocumab-on-major-cardiovascular-events-in-patients-with-an-acute-coronary-syndrome-to-be-presented-at-the-america/

 

20.2.6 Cholesterol Lowering Novel PCSK9 drugs: Praluent [Sanofi and Regeneron] vs Repatha [Amgen] – which drug cuts CV risks enough to make it cost-effective?

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/03/12/cholesterol-lowering-novel-pcsk9-drugs-praluent-sanofi-and-regeneron-vs-repatha-amgen-which-drug-cuts-cv-risks-enough-to-make-it-cost-effective/

 

20.2.7 Inflammatory Disorders: Articles published @pharmaceuticalintelligence.com

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/02/28/inflammatory-disorders-articles-published-pharmaceuticalintelligence-com/

20.3 Inflammation independent of Lipid level in CAD

 

20.3.1 Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation

Curator, Author, Writer, Reporter: Larry Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/10/08/statins-nonlipid-effects-on-vascular-endothelium-through-enos-activation/

 

20.3.2 Long-term Canakinumab Treatment Lowering Inflammation Independent of Lipid Levels for Residual Inflammatory Risk Benefit – Personalized Medicine for Recurrent MI, Strokes and Cardiovascular Death

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/11/21/long-term-canakinumab-treatment-lowering-inflammation-independent-of-lipid-levels-for-residual-inflammatory-risk-benefit-personalized-medicine-for-recurrent-mi-strokes-and-cardiovascular-death/

 

20.3.3 Cigarette smoke induces pro-inflammatory cytokine release by activation of NF-kappaB and post-translational modifications of histone deacetylase as seen in macrophages

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

https://pharmaceuticalintelligence.com/2013/05/19/cigarette-smoke-induces-pro-inflammatory-cytokine-release-by-activation-of-nf-kappab-and-posttranslational-modifications-of-histone-deacetylase-as-seen-in-macrophages/

 

20.3.4 The Future of Translational Medicine with Smart Diagnostics and Therapies: PharmacoGenomics

Curator: Demet Sag, PhD

https://pharmaceuticalintelligence.com/2014/03/05/the-future-of-translational-medicine-with-smart-diagnostics-and-therapies-pharmacogen

 

Summary to Part Two

by Justin D. Pearlman, MD, PhD, FACC 

Part Two of this Volume on Pharmaceuticals in cardiovascular disease focused on biomarkers – indicators of disease status. Chapter 15 presented recent new examples, such as brain naturetic peptide and high-sensitivity troponin. Chapter 16 addressed how the completion of the mapping of the human genome paves the way for identifying many more biomarkers. Chapter 17 reviewed biomarker utility in various disease conditions. Chapter 18 reviewed biomarker utility in acute disorders. Chapter 19 looked at biomarkers in relation to cholesterol, lipids, diet and impact of supplements. Chapter 20 examined biomarkers of inflammation.

 

EPILOGUE

by Justin D. Pearlman, MD, PhD, FACC 

Pharmaceutical management of cardiovascular disease is a broad complex topic encompassing diagnostics (biomarkers) and therapies (medications). Although some clinicians may hope to simplify the process to just picking a fixed dose of their favorite medicine for a given diagnosis, the optimal approach is far more nuanced, requiring an understanding of numerous interactions, alignment of choices with individual particulars, and optimization of dosing based on evaluation of response. Insurance companies often favor fixed dosing and may impede optimization by not authorizing a dose higher than their “standard.”

In general, cardiovascular medications may be titrated (increased step-wise) to optimize the benefit, increasing until the desired goal is achieved, unless limited by side effects, a plateau (saturation, no further benefit), or excess risk. If a patient qualifies for a beta blocker due to high heart rates with heart failure, for example, a responsible clinician will consider whether to use a lipophilic beta blocker that crosses the blood brain barrier (and may reduce migraines and tremor but may worsen depression), as well as the importance of high selectivity to avoid blocking beta-2 along with beta-1 and potentially aggravating airway disease (asthma, COPD), in addition to considering the “unopposed alpha” biofeedback response to beta blockers which can promote vascular spasms that may worsen Prinzmetal’s angina (cocaine users have elevated risk), migraines, coldness of extremities and Raynaud’s disease.

For example, if a patient is prescribed slow release metoprolol, heart rate or blood pressure response may limit them to 12.5 mg daily while other patients may require 200 mg/day, due to individual differences in body distribution, receptor density, sensitivity to the agent, destruction and elimination rates. For those taking the short acting metoprolol tartrate, despite vendor promotion of “BID” (twice daily dosing), close monitoring of patient response shows many patients are only effectively treated for 6-8 hours, and therefore get elevated heart rates and/or undesirable hypertension twice daily for 4-6 hours when the medication wears off. Hopefully, you have learned from this Volume that the optimal use of pharmaceuticals, whether as markers or as therapy, pays attention to many factors, checks duration and benefit versus risk for each application, and takes advantage of methods presented to achieve optimal benefits.

The approach of this Volume is Curation of original sources with periodic updates, so come back and revisit this to track how knowledge of this topic evolves.