View on Amazon.com
https://www.amazon.com/dp/B0BPRCZ1QF
Audio y Texto
- Original Volume Five: Pharmacological Agents in Treatment of Cardiovascular Diseases
-
NEW GENRE Volume Five: Pharmacological Agents in Treatment of Cardiovascular Diseases
This volume has the following three parts:
PART A: The eTOCs in Spanish in Audio format
PART B: The eTOCs in Bi-lingual format: Spanish and English in Text format
PART C: The Editorials of the original e-Books in English in Audio format
PART A: The eTOCs in Spanish in Audio format
Serie A: libros electrónicos acerca de las enfermedades cardiovasculares
QUINTO VOLUMEN
Agentes farmacológicos en el tratamiento de las enfermedades cardiovasculares
(LIBRO 5 DE LA SERIE DE LIBROS ELECTRÓNICOS SOBRE BIOMEDICINA)
Traducción a español
Disponible en Amazon.com desde el 23/12/2018
https://www.amazon.com/dp/B07MGSFDWR
Justin D. Pearlman, MD, PhD, FACC
y
Leaders in Pharmaceutical Business Intelligence
avivalev-ari@alum.berkeley.edu
Redactora jefe
Indice de contenidos electrónico (IDCe)
Los enlaces indicados llevan al contenido original en inglés
| MD | Licenciado/a en medicina y cirugía (Estados Unidos) |
| PhD | Doctorado/a |
| RN | Enfermero/a titulado/a |
| FCAP | Miembro distinguido del Colegio de anatomopatólogos de los Estados Unidos |
| FACC | Miembro distinguido del Colegio de cardiólogos de los Estados Unidos |
PREFACIO
por Justin D. Pearlman, MD, PhD, FACC
Listado de colaboradores
Clasificación de los medicamentos cardíacos: perspectiva general de las mejores prácticas en Estados Unidos por acción y uso, medicamentos comunes, contraindicaciones, interacciones con otros medicamentos, efectos secundarios y efectos adversos
Reportero y editor: Aviva Lev-Ari, PhD, RN
Primera parte
Diagnósticos cardiovasculares y tratamiento farmacológico
Introducción a la primera parte por Justin D. Pearlman, MD, PhD, FACC
Capítulo 1: Tendencias nacionales: estancia hospitalaria por causas cardiovasculares, coste del tratamiento y carga social
Capítulo 2: Introducción a los tipos de medicamentos: marcas de nueva aparición, genéricos, agentes biológicos y biosimilares
Capítulo 3: Antiinflamación e inflamación sistémica
Capítulo 4: Clase de fármacos antitrombóticos y nuevos anticoagulantes orales (NACO)
Capítulo 5: Respuesta farmacogenética a las mutaciones congénitas y espontáneas: nuevos fármacos para la aterosclerosis, novedosos agentes genéticos frente a colesterol, lípidos, LDL, HDL, hipertrigliceridemia e hiperlipidemia
Capítulo 6: Epigenética, diferencias entre sexos y estilo de vida: DM, obesidad, marcadores hormonales, dietas, cronoterapia
Capítulo 7: Control de la tensión arterial: genética e inmunidad adaptativa humana
Capítulo 8: Fármacos antiarrítmicos: fibrilación auricular (FA) e infartos cerebrales silentes
Capítulo 9: IM, síndrome coronario agudo (SCA) e insuficiencia cardíaca (IC)
Capítulo 10: Calcio y enfermedades cardiovasculares: disfunción contráctil, el calcio como sensor de neurotransmisores
Capítulo 11: Regeneración: sistema cardíaco (cardiomiogénesis) y vasculatura (angiogénesis)
Capítulo 12: Biología vascular, ateroesclerosis y cardiología molecular
Capítulo 13: Farmacogenómica en las enfermedades cardiovasculares
Capítulo 14: Efectos adversos y toxicidad de los medicamentos
Resumen de la primera parte por Justin D. Pearlman, MD, PhD, FACC
Segunda parte
Los biomarcadores como factores diagnósticos y determinantes de la selección de agentes terapéuticos
Introducción a la segunda parte por Justin D. Pearlman, MD, PhD, FACC
Capítulo 15: El papel de los biomarcadores en la farmacoterapia. Avances en el desarrollo de biomarcadores para las enfermedades cardiovasculares
Capítulo 16: Empleo de la genómica para el diagnóstico de enfermedades
Capítulo 17: Biomarcadores por indicación médica y diagnóstico
Capítulo 18: Episodios cardíacos urgentes. El papel de los biomarcadores en el tratamiento
Capítulo 19: Biomarcadores para evaluar la dislipidemia, el papel de la dieta y los suplementos
Capítulo 20: Biomarcadores para detectar la inflamación
Resumen de la segunda parte por Justin D. Pearlman, MD, PhD, FACC
EPÍLOGO por Justin D. Pearlman, MD, PhD, FACC
Agentes farmacológicos en el tratamiento de las enfermedades cardiovasculares
(LIBRO 5 DE LA SERIE DE LIBROS ELECTRÓNICOS SOBRE BIOMEDICINA)
Pharmacological Agents in Treatment of Cardiovascular Diseases
Disponible en Amazon.com desde el 23/12/2018
2018
https://www.amazon.com/dp/B07MGSFDWR
PART B: The eTOCs in Bi-lingual format:
Spanish and English in Text format
Serie A: libros electrónicos acerca de las enfermedades cardiovasculares
QUINTO VOLUMEN
Agentes farmacológicos en el tratamiento de las enfermedades cardiovasculares
(LIBRO 5 DE LA SERIE DE LIBROS ELECTRÓNICOS SOBRE BIOMEDICINA)
Traducción a español Montero Language Services
Disponible en Amazon.com desde el 23/12/2018
https://www.amazon.com/dp/B07MGSFDWR
Justin D. Pearlman, MD, PhD, FACC
Editorials and Clinical Pearls, Author
y
Leaders in Pharmaceutical Business Intelligence
avivalev-ari@alum.berkeley.edu
Redactora jefe
Series A: e-Books on Cardiovascular Diseases
VOLUME FIVE
Pharmacological Agents in Treatment of Cardiovascular Diseases
(BIOMED E-BOOKS BOOK 5)
Available on Amazon.com since 12/23/2018
2018
https://www.amazon.com/dp/B07MGSFDWR
Justin D. Pearlman, MD, PhD, FACC
Editorials and Clinical Pearls, Author
and
Leaders in Pharmaceutical Business Intelligence
avivalev-ari@alum.berkeley.edu
Editor-in-Chief
Indice de contenidos electrónico (IDCe)
electronic Table of Contents
Los enlaces indicados llevan al contenido original en inglés
| MD | Licenciado/a en medicina y cirugía (Estados Unidos) |
| PhD | Doctorado/a |
| RN | Enfermero/a titulado/a |
| FCAP | Miembro distinguido del Colegio de anatomopatólogos de los Estados Unidos |
| FACC | Miembro distinguido del Colegio de cardiólogos de los Estados Unidos |
PREFACIO
por Justin D. Pearlman, MD, PhD, FACC
PREFACE
by Justin D. Pearlman, MD, PhD, FACC
Listado de colaboradores
List of Contributors
PREFACE, Introduction to Part One, Summary to Part One, Introduction to Part Two, Summary to Part Two, EPILOGUE and Clinical Pearls
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
| 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
15.4, 17.3.11, 19.1.7, 19.1.8, 19.1.9, 20.3.3
15.10, 16.9, 20.3.4
4.12
Clasificación de los medicamentos cardíacos: perspectiva general de las mejores prácticas en Estados Unidos por acción y uso, medicamentos comunes, contraindicaciones, interacciones con otros medicamentos, efectos secundarios y efectos adversos
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
Reportero y editor: Aviva Lev-Ari, PhD, RN
Reporter and Curator: Aviva Lev-Ari, PhD, RN
Primera parte
Diagnósticos cardiovasculares y tratamiento farmacológico
Part One
Cardiovascular Diagnoses and Pharmacological Therapy
Introducción a la primera parte por Justin D. Pearlman, MD, PhD, FACC
Introduction to Part One by Justin D. Pearlman, MD, PhD, FACC
Capítulo 1: Tendencias nacionales: estancia hospitalaria por causas cardiovasculares, coste del tratamiento y carga social
Chapter 1: National Trends: Cardiovascular-related Hospital stay, Cost of Treatment & Societal Burden
Capítulo 2: Introducción a los tipos de medicamentos: marcas de nueva aparición, genéricos, agentes biológicos y biosimilares
Chapter 2: Introduction to Drug Types: De Novo Brand, Generic, Biologics, Biosimilars
Capítulo 3: Antiinflamación e inflamación sistémica
Chapter 3: Anti-Inflammatory & Systemic Inflammatory
Capítulo 4: Clase de fármacos antitrombóticos y nuevos anticoagulantes orales (NACO)
Chapter 4: Anti-thrombotic Drug Class & Novel Oral Anticoagulants (NOACs)
Capítulo 5: Respuesta farmacogenética a las mutaciones congénitas y espontáneas: nuevos fármacos para la aterosclerosis, novedosos agentes genéticos frente a colesterol, lípidos, LDL, HDL, hipertrigliceridemia e hiperlipidemia
Chapter 5: Pharmaco-Genetics response to Congenital and Spontaneous Mutations: new drugs for Atherosclerosis, Genetic-related Novel Anti-Cholesterol, Lipids, LDL, HDL, Hypertriglyceridemia Hyperlipidemia
Capítulo 6: Epigenética, diferencias entre sexos y estilo de vida: DM, obesidad, marcadores hormonales, dietas, cronoterapia
Chapter 6: Epigenetics, Gender differences and Life Style: DM, Obesity, Hormonal Markers, Diets, Chrono-therapeutics
Capítulo 7: Control de la tensión arterial: genética e inmunidad adaptativa humana
Chapter 7: Blood Pressure Management: Genetics & Human Adaptive Immunity
Capítulo 8: Fármacos antiarrítmicos: fibrilación auricular (FA) e infartos cerebrales silentes
Chapter 8: Anti-arrhythmic Drugs – Atrial Fibrillation (AF) & Silent Cerebral Infarctions
Capítulo 9: IM, síndrome coronario agudo (SCA) e insuficiencia cardíaca (IC)
Chapter 9: MI, Acute Coronary Syndrome (ACS) and Heart Failure (HF)
Capítulo 10: Calcio y enfermedades cardiovasculares: disfunción contráctil, el calcio como sensor de neurotransmisores
Chapter 10: Calcium & Cardiovascular Diseases: Contractile Dysfunction, Calcium as Neurotransmitter Sensor
Capítulo 11: Regeneración: sistema cardíaco (cardiomiogénesis) y vasculatura (angiogénesis)
Chapter 11: Regeneration: Cardiac System (cardiomyogenesis) and Vasculature (angiogenesis)
Capítulo 12: Biología vascular, ateroesclerosis y cardiología molecular
Chapter 12: Vascular Biology, Atherosclerosis and Molecular Cardiology
Capítulo 13: Farmacogenómica en las enfermedades cardiovasculares
Chapter 13: PharmacoGenomics in Cardiovascular Disease
Capítulo 14: Efectos adversos y toxicidad de los medicamentos
Chapter 14: Drug Adverse Effects and Toxicity
Resumen de la primera parte por Justin D. Pearlman, MD, PhD, FACC
Summary to Part One by Justin D. Pearlman, MD, PhD, FACC
Segunda parte
Los biomarcadores como factores diagnósticos y determinantes de la selección de agentes terapéuticos
Part Two
Biomarkers as Diagnostics and Determinants in Therapeutics Selection
Introducción a la segunda parte por Justin D. Pearlman, MD, PhD, FACC
Introduction to Part Two by Justin D. Pearlman, MD, PhD, FACC
Capítulo 15: El papel de los biomarcadores en la farmacoterapia. Avances en el desarrollo de biomarcadores para las enfermedades cardiovasculares
Chapter 15: The Role of Biomarkers in Pharmacotherapy – Breakthroughs in Biomarker Development for Cardiovascular Disease
Capítulo 16: Empleo de la genómica para el diagnóstico de enfermedades
Chapter 16: Genomics Harnessed for Disease Diagnosis
Capítulo 17: Biomarcadores por indicación médica y diagnóstico
Chapter 17: Biomarkers by Medical Indication and Diagnosis
Capítulo 18: Episodios cardíacos urgentes. El papel de los biomarcadores en el tratamiento
Chapter 18: Emergent Cardiac Events – The Role of Biomarkers in Treatment
Capítulo 19: Biomarcadores para evaluar la dislipidemia, el papel de la dieta y los suplementos
Chapter 19: Biomarkers for Assessment of Dyslipidemia, the role of Diet and Supplements
Capítulo 20: Biomarcadores para detectar la inflamación
Chapter 20: Biomarkers for Inflammation Detection
Resumen de la segunda parte por Justin D. Pearlman, MD, PhD, FACC
Summary to Part Two by Justin D. Pearlman, MD, PhD, FACC
EPÍLOGO por Justin D. Pearlman, MD, PhD, FACC
EPILOGUE by Justin D. Pearlman, MD, PhD, FACC
Agentes farmacológicos en el tratamiento de las enfermedades cardiovasculares
(LIBRO 5 DE LA SERIE DE LIBROS ELECTRÓNICOS SOBRE BIOMEDICINA)
Pharmacological Agents in Treatment of Cardiovascular Diseases
Disponible en Amazon.com desde el 23/12/2018
2018
https://www.amazon.com/dp/B07MGSFDWR
PART C:
The Editorials of the original e-Books in
English in Audio format
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, counter-activity), 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 heart rate and blood pressure, for example, leads to up-regulation 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 content 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
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/
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
Part One
Cardiovascular Diagnoses and Pharmacological Therapy
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.
THE VOICE OF Dr. Justin Pearlman, MD, PhD, FACC IS FOUND IN ITALICS BELOW, as an active Cardiologist treating patients and as a renown expert on cardiovascular diseases.
Chapter 1
National Trends: Cardiovascular-related Hospital stay, Cost of Treatment & Societal Burden
Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support System
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.
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.
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.
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.”
This next link ranks the biggest contributions to hospitalization costs, with heart valve disease at the top, averaging over $40,000 per visit.
As reported below, use of antihypertensive medication by diabetics significantly reduces their need for costly hospitalization stays.
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.
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.
Chapter 2
Introduction to Drug Types: Brand, Generic, Biologics, Biosimsilars
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.
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/
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.
Chapter 3
Anti-Inflammatory & Systemic Inflammatory
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.
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.
Chapter 4
Anti-Thrombotic Drug Class & Novel Oral Anticoagulants (NOACs)
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.
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.
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.
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.”
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.
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. Sedimentation 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.
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).
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.
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).
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.
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.
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.
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.
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
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
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).
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.
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).
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.
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.
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.
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%).
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
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.
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.
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.
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 (breakeven), 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.
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).
Chapter 6
Epigenetics, Gender differences and Life Style: DM, Obesity, Hormonal Markers, Diets, Chrono-therapeutics
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).
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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).
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.
Chapter 8
Anti-arrhythmic Drugs: Atrial Fibrillation (AF) & Silent Cerebral Infarctions
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.
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.
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.
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.
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.
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:
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.
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.
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.
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.
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%.
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.
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.
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
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.
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.
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).
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.
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.
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-dependent Syt1 (C) domain of protein-kinase C isoenzyme, which binds to phospholipids.
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.
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.
Chapter 11
Regeneration: Cardiac System (cardiomyogenesis) and Vasculature (angiogenesis)
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.
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.
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.
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.
Chapter 12
Vascular Biology, Atherosclerosis and Molecular Cardiology: Vasculogenesis, Angiogenesis, and Arteriogenesis
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.
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 NO2.
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.
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.
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.
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 Endothelial 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.
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
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.
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.
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